RU2562232C2 - Novel cc-1065 analogues and their conjugates - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to formula

compound or its pharmaceutically acceptable salt, where DB represents DNA-binding group and represents group

DB1, R¹ represents halogen; R², R^2', R³, R^3', R⁴, R^4', R¹² and R¹⁹ represent H, X² represents C(R¹⁴)(R^14') and where R^14' and R^7' are absent, which results in double bond between atoms, carrying R^7' and R^14'; R⁵, R⁶ and R⁷ are independently selected from H and R^e, where R^e is selected from C_1-3alkyl; R^5'+R^6' are absent, which results in double bond between atoms, carrying R^5'′ and R^6'; X¹ represents O; X³ is selected from N and NR¹⁵; X⁴ represents CR¹⁶; X⁵ represents O; X⁶ is selected from CR¹¹, CR¹¹(R^11') and N; X⁷ is selected from CR⁸, CR⁸(R^8'), NR⁸ and N; X⁸ is selected from CR⁹, CR⁹(R^9′), NR⁹ and N; X⁹ is selected from CR¹⁰, CR¹⁰(R^10′) and N; X¹¹ represents C; X¹² is selected from C and N; X³⁴ represents C;

supposes that said bond can be optionally delocalised, double bond; R⁸ represents H and N(R^h)C(O)Rⁱ; R⁸, R⁹, R^9', R¹⁰, R^10', R¹¹, R^11', R¹⁵, R^16' represent H, R^h represents H; Rⁱ is selected from C₆-C₉aryl and indole, substituted with one or several substituents, selected from OH, NH₂, (CH₂CH₂O)_2-4H and O(CH₂CH₂O)_2-4CH₃; a and b are independently selected from 0 and 1; on condition that ring B in DB1 represents heterocycle. Invention also relates to pharmaceutical composition for treatment or prevention of tumour in mammals, containing therapeutically efficient quantity of formula (I) compound. Formula (I) compound, conjugated with antibody, represents conjugate for treatment or prevention of tumour.

EFFECT: analogues of DNA-alkylating CC-1065 preparation and their analogues.

7 cl, 14 dwg, 1 tbl, 23 ex

Description

FIELD OF THE INVENTION

The present invention relates to new analogues of the DNA-alkylating agent CC-1065 and their conjugates. In addition, the present invention relates to intermediates for the preparation of said agents and conjugates. Conjugates are intended to release their (multiple) effective moiety after one or more stages of activation and / or at a speed and time interval controlled by the conjugate, for the selective delivery and / or controlled release of one or more of these DNA alkylating agents. Means, conjugates and intermediates can be used to treat diseases characterized by undesired (cell) proliferation. For example, the agents and conjugates of the present invention can be used to treat tumors.

BACKGROUND

Duocarmycins, which were first isolated from a culture broth of the Streptomyces species, are members of the antitumor antibiotic family, which also includes CC-1065. These extremely effective substances, apparently, show their biological activity due to the ability to selectively alkylate the DNA sequence on the N3 of the minor furrow adenine, which triggers a cascade of events leading to the triggering of apoptotic cell death. ^one

Although CC-1065 showed very strong cytotoxicity, it could not be used in the clinic due to significant delayed hepatotoxicity. ² This observation led to the development of synthetic analogues of CC-1065 (see derivatives of CC-1065, for example, Aristoff et al. , J. Org. Chem. 1992 , 57 , 6234; Boger et al. , Bioorg. Med. Chem. Lett . 1996 , 6 , 2207; Boger et al. , Chem. Rev. 1997 , 97 , 787; Milbank et al. , J. Med. Chem. 1999 , 42 , 649; Atwell et al. , J. Med. Chem. 1999 , 42 , 3400; Wang et al. , J. Med. Chem. 2000 , 43 , 1541; Boger et al. , Bioorg. Med. Chem. Lett 2001 , 11 , 2021; Parrish et al. , Bioorg. Med. Chem. 2003 , 11 , 3815; Daniell et al. , Bioorg. Med. Chem. Lett. 2005 , 15 , 177; Tichenor et al. , J. Am. Chem. Soc. 2006 , 128 , 15683; Purnell et al. , Bioorg. Med. Chem. 2006 , 16 , 5677; Bando and Sugiyama, Acc. Chem. Res. 2006 , 39 , 935; Tichenor et al. , Nat. Prod. Rep. 2008 , 25 , 220; MacMillan et al. , J. Am. Chem. Soc. 2009 , 131 , 1187; Tietze et al. , Anti-Cancer Agents Med. Chem. 2009 , 9 , 304; Gauss et al. , Tetrahedron 2 009 , 65 , 6591; EP 0154445; WO 88/04659; WO 90/02746; WO 97/12862; WO 97/32850; WO 97/45411; WO 98/52925; WO 99/19298; WO 01/83482; WO 02/067937; WO 02/067930; WO 02/068412; WO 03/022806; WO 2004/101767; WO 2006/043839, and WO 2007/051081), which usually show similar cytotoxicity but reduced hepatotoxicity. However, these derivatives still do not have sufficient selectivity for tumor cells, since the selectivity of these agents - and cytotoxic agents in general - is in some way based on the difference in the proliferation rate of tumor and normal cells, and, accordingly, they also affect healthy cells that exhibit a relatively high proliferation rate. This usually leads to severe side effects. Drug concentrations that would completely eradicate the tumor cannot be achieved due to dose-limiting side effects, such as toxicity to the gastrointestinal tract and bone marrow. In addition, tumors may develop resistance to anti-cancer agents after prolonged treatment. Thus, in the development of modern drugs, targeting cytotoxic drugs to the tumor site can be considered as one of the main tasks.

In one of the promising approaches for obtaining increased selectivity for tumor cells or tumor tissues, the existence of tumor-related antigens, receptors and other receptive elements that can serve as a target should be used. Such a goal can increase the controllability or, to some extent, be specifically present in the tumor tissue or in nearby tissue, such as neovascular tissue, relative to other tissues to achieve effective targeting. A large number of goals have been identified and evaluated, and several methods have been developed for identifying and evaluating goals. ³ By binding a ligand, for example, an antibody or antibody fragment, for such a tumor-associated antigen, receptor or other receptive element to a therapeutic agent, the agent can selectively target the tumor tissue.

Another promising approach to achieve selectivity for tumor cells or tumor tissue is to use the presence of tumor-related enzymes. An enzyme that is located mainly on the site of the tumor can convert a pharmacologically inactive prodrug, which consists of an enzyme substrate, directly or indirectly associated with a toxic drug, to the corresponding drug in or within the tumor. In this method, a high concentration of a toxic agent against a malignant tumor can be selectively achieved at the site of the tumor. If the dose is high enough, all tumor cells can be killed, which can reduce the spread of drug-resistant tumor cells.

Enzymes can also be transported to the surrounding area or to target cells or target tissues by, for example, antibody-directed enzymatic prodrug therapy (ADEPT) ⁴ , polymer-directed enzymatic prodrug therapy (PDEPT) or macromolecule-targeted enzymatic prodrug therapy (MDEPT) ⁵ , virus-directed enzyme prodrug therapy (VDEPT) ⁶ or gene-directed enzyme prodrug therapy (GDEPT) ⁷ . Using ADEPT, for example, a non-toxic prodrug is selectively converted to a cytoxic compound on the surface of target cells by an antibody-enzyme conjugate that has previously been targeted to the surface of these cells.

Another promising approach for obtaining selectivity for tumor cells or tumor tissue uses the effect of enhanced permeability and delay (EPR). Due to this effect, EPR macromolecules passively accumulate in solid tumors as a result of the disorganized pathology of the tumor angiogenic vasculature with its intermittent endothelium, leading to hyperpermeability for large macromolecules and a lack of effective lymphatic drainage of the tumor. ⁸ When binding a therapeutic agent directly or indirectly to a macromolecule, said agent may selectively target tumor tissue.

In addition to effective targeting, other important criteria for the successful use of targeted conjugates of cytotoxic agents in tumor therapy are such that one or more agents is effectively released from the conjugate at the site of the tumor, and that the conjugate is non-cytotoxic or only very slightly cytotoxic, while the cytotoxic agent itself demonstrates very strong cytotoxicity. In the ideal case, this leads to the formation of cytotoxic molecules only on the site of the tumor, which gives a significantly increased therapeutic index relative to the unarmed cytotoxic agent. Another important criterion for a successful targeted conjugate is that the conjugate has suitable pharmacological properties, such as sufficient stability in the bloodstream, a tendency to low aggregation, and good water solubility. Suitable water solubility and hydrophilicity of the drug and / or linker may contribute to the improvement of pharmacological properties.

Some conjugates of CC-1065 and derivatives have been described (see conjugates of derivatives of CC-1065, for example, Suzawa et al. , Bioorg. Med. Chem. 2000 , 8 , 2175; Jeffrey et al. , J. Med. Chem. 2005 , 48 , 1344; Wang et al. , Bioorg. Med. Chem. 2006 , 14 , 7854; Tietze et al. , Chem. Eur. J. 2007 , 13 , 4396; Tietze et al. , Chem. Eur. J. 2008 , 14 , 2811; Tietze et al. , ChemMedChem 2008 , 3 , 1946; Li et al., Tetrahedron Lett. 2009 , 50 , 2932; WO 91/16324; WO 94/04535; WO 95/31971; US 5475092; US 5585499; US 5646298; WO 97/07097; WO 97/44000; US 5739350; WO 98/11101; WO 98/25898; US 5843937; US 5846545; WO 02/059122; WO 02/30894; WO 03/086318; WO 2005/103040; WO 2005/112919; WO 2006/002895; WO 2006/110476; WO 2007/038658; WO 2007/059404; WO 2008/083312; WO 2008/103693; WO 2009/026274, and WO 2009/064908) . In these conjugates, one or more of the beneficial properties discussed above may not be optimal.

Accordingly, there is still an obvious need for conjugates of CC-1065 derivatives that show high cytotoxicity (i.e., IC _{50, conjugate} / IC _{50, parent drug} ), contain CC-1065 derivatives having strong cytotoxicity and favorable pharmacological properties, and derivatives of CC-1065 were efficiently released.

SUMMARY OF THE INVENTION

The present invention satisfies the above need and relates to a compound of formula ( I ) or ( II ):

,

,

or its pharmaceutically acceptable salt, hydrate or MES, where

DB is a DNA binding group and is selected from the group consisting of

;

;

R ¹ represents a leaving group;

R ² , R ^{2 '} , R ³ , R ^3' , R ⁴ , R ^{4 '} , R ¹² and R ^{19 are} independently selected from H, OH, SH, NH ₂ , N ₃ , NO ₂ , NO, CF ₃ , CN , C (O) NH ₂ , C (O) H, C (O) OH, halogen, R ^a , SR ^a , S (O) R ^a , S (O) ₂ R ^a , S (O) OR ^a , S (O) ₂ OR ^a , OS (O) R ^a , OS (O) ₂ R ^a , OS (O) OR ^a , OS (O) ₂ OR ^a , OR ^a , NHR ^a , N (R ^a ) R ^b , ⁺ N (R ^a ) (R ^b ) R ^c , P (O) (OR ^a ) (OR ^b ), OP (O) (OR ^a ) (OR ^b ), SiR ^a R ^b R ^c , C ( O) R ^a , C (O) OR ^a , C (O) N (R ^a ) R ^b , OC (O) R ^a , OC (O) OR ^a , OC (O) N (R ^a ) R ^b , N (R ^a ) C (O) R ^b , N (R ^a ) C (O) OR ^b and N (R ^a ) C (O) N (R ^b ) R ^c , where

R ^a , R ^b and R ^{c are} independently selected from H and optionally substituted C _1-3 alkyl or C _1-3 heteroalkyl,

or R ³ + R ^{3 '} and / or R ⁴ + R ^{4' are} independently selected from = O, = S, = NOR ¹⁸ , = C (R ¹⁸ ) R ^{18 '} and = NR ¹⁸ , R ¹⁸ and R ^18' independently selected from H and optionally substituted C _1-3 alkyl, two or more R ² , R ^{2 '} , R ³ , R ^3' , R ⁴ , R ^{4 '} and R ^{12 are} optionally joined by one or more bonds to form one or more optionally substituted carbocycles and / or heterocycles;

X ² selected from O, C (R^fourteen) (R^fourteen') and NR^fourteen'where R^fourteen and R^fourteen' have the same meaning as defined for R⁷, and are independently selected, or R^fourteen' and R^{7 '} are absent, which gives a double bond between the atoms, which, as provided, carry R^{7 '} and R^fourteen';

R ⁵ , R ^{5 '} , R ⁶ , R ^6' , R ⁷ and R ^{7 'are} independently selected from H, OH, SH, NH ₂ , N ₃ , NO ₂ , NO, CF ₃ , CN, C (O) NH ₂ , C (O) H, C (O) OH, halogen, ^Re , SR ^e , S (O) ^Re , S (O) ₂ ^Re , S (O) OR ^e , S (O) ₂ OR ^e , OS (O) R ^e , OS (O) ₂ R ^e , OS (O) OR ^e , OS (O) ₂ OR ^e , OR ^e , NHR ^e , N (R ^e ) R ^f , ⁺ N (R ^e ) (R ^f ) R ^g , P (O) (OR ^e ) (OR ^f ), OP (O) (OR ^e ) (OR ^f ), SiR ^e R ^f R ^g , C (O) R ^e , C (O) OR ^e , C (O) N (R ^e ) R ^f , OC (O) R ^e , OC (O) OR ^e , OC (O) N (R ^e ) R ^f , N (R ^e ) C (O) R ^f , N (R ^e ) C (O) OR ^f , N (R ^e ) C (O) N (R ^f ) R ^g and a water-soluble group, where

R ^e , R ^f and R ^{g are} independently selected from H and optionally substituted (CH ₂ CH ₂ O) _ee CH ₂ CH ₂ X ¹³ R ^e1 , C _1-15 alkyl, C _1-15 heteroalkyl, C _3-15 cycloalkyl, C _1-15 heterocycloalkyl, C _5-15 aryl or C _1-15 heteroaryl, where ee is 1-1000, X ^{13 is} selected from O, S and NR ^f1 , and R ^f1 and R ^{e1 are} independently selected from H and C _{1- 3} alkyl, one or more optional substituents R ^e , R ^f and / or R ^g are optionally a water-soluble group, two or more ^Re , R ^f and R ^{g are} optionally joined by one or more bonds to form one or more optionally substituted carbocycles and / or heterocytes Clove

or R ⁵ + R ^{5 '} and / or R ⁶ + R ^6' and / or R ⁷ + R ^{7 'are} independently selected from = O, = S, = NOR ^e3 , = C (R ^e3 ) R ^e4 and = NR ^e3 , R ^e3 and R ^{e4 are} independently selected from H and optionally substituted C _1-3 alkyl, or R ^{5 ′} + R ^{6 ′} and / or R ^{6 ′} + R ^{7 ′} and / or R ^{7 ′} + R ^{14 ′ are} absent, which gives a double bond between the atoms, which are defined as bearing R ^{5 '} and R ^6' and / or R ^{6 '} and R ^7' and / or R ^{7 '} and R ^14' , respectively, two or more of R ⁵ , R ^{5 '} , R ⁶ , R ^{6 '} , R ⁷ , R ^7' , R ¹⁴ and R ^{14 'are} optionally joined by one or more bonds to form one or more optionally substituted carbocycles and / or heterocycles;

X ^{1 is} selected from O, S, and NR ¹³ , where R ^{13 is} selected from H and optionally substituted C _1-8 alkyl or C _1-8 heteroalkyl and are not connected to other substituents;

X ³ selected from O, S, C (R^fifteen) R^fifteen', -C (R^fifteen) (R^fifteen') -C (R^fifteen'') (R^fifteen''') -, -N (R^fifteen) -N (R^fifteen') -, -C (R^fifteen) (R^fifteen') -N (R^fifteen'') -, -N (R^fifteen'') -C (R^fifteen) (R^fifteen') -, -C (R^fifteen) (R^fifteen') -O-, -O-C (R^fifteen) (R^fifteen') -, -C (R^fifteen) (R^fifteen') -S-, -S-C (R^fifteen) (R^fifteen') -, -C (R^fifteen) = C (R^fifteen') -, = C (R^fifteen) -C (R^fifteen') =, -N = C (R^fifteen') -, = N-C (R^fifteen') =, -C (R^fifteen) = N-, = C (R^fifteen) -N =, -N = N-, = N-N =, CR^fifteen, N and NR^fifteen, or inDB1 andDB2 -X ³- represents -X ^3a andX ^3b- whereX ^3a connected toX ³⁴a double bond is present betweenX ³⁴ andX ^four , andX ^3b connected toX ^eleven, WhereX ^3a independently selected from H and optionally substituted (CH₂CH₂O)_eeCH₂CH₂ X ¹³R^e1, C_1-8 alkyl or C_1-8 heteroalkyl and is not connected to other substituents;

X ^{4 is} selected from O, S, C (R ¹⁶ ) R ^{16 '} , NR ¹⁶ , N, and CR ¹⁶ ;

X ^{5 is} selected from O, S, C (R ¹⁷ ) R ^{17 ′} , NOR ¹⁷ and NR ¹⁷ , where R ¹⁷ and R ^{17 ′ are} independently selected from H and optionally substituted C _1-8 alkyl or C _1-8 heteroalkyl and not connected to other substituents;

X ^{6 is} selected from CR ¹¹ , CR ¹¹ (R ^{11 ′} ), N, NR ¹¹ , O, and S;

X ^{7 is} selected from CR ⁸ , CR ⁸ (R ^{8 '} ), N, NR ⁸ , O, and S;

X ^{8 is} selected from CR ⁹ , CR ⁹ (R ^{9 '} ), N, NR ⁹ , O, and S;

X ^{9 is} selected from CR ¹⁰ , CR ¹⁰ (R ^{10 ′} ), N, NR ¹⁰ , O, and S;

X ^{10 is} selected from CR ²⁰ , CR ²⁰ (R ^{20 '} ), N, NR ²⁰ , O, and S;

X ^{11 is} selected from C, CR ²¹ and N, or X ¹¹ —X ^{3b is} selected from CR ²¹ , CR ²¹ (R ^{21 ′} ), N, NR ²¹ , O, and S;

X ^{12 is} selected from C, CR ²² and N;

X ^{6 *},X ^{7 *},X ^8*,X ^9*,X ^10* andX ^eleven* have the same meanings as defined forX ⁶,X ⁷,X ⁸,X ⁹,X ¹⁰ andX ^eleven, respectively, and are independently selected;

X ^{34 is} selected from C, CR ²³ and N;

the X ¹¹ atom of ring B in DB6 and DB7 is connected to the ring atom of ring A so that ring A and ring B in DB6 and DB7 are directly connected via a direct link;

означает, что указанная связь может быть одинарной связью или неаккумулированной, необязательно делокализованной, двойной связью;

means that said bond may be a single bond or an unaccumulated, optionally delocalized, double bond;

each R ⁸ , R ^{8 '} , R ⁹ , R ^9' , R ¹⁰ , R ^{10 '} , R ¹¹ , R ^11' , R ¹⁵ , R ^{15 '} , R ^15'' , R ^15''' , R ¹⁶ , R ^{16 '} , R ²⁰ , R ^20' , R ²¹ , R ^{21 '} , R ²² and R ^{23 are} independently selected from H, OH, SH, NH ₂ , N ₃ , NO ₂ , NO, CF ₃ , CN, C ( O) NH ₂ , C (O) H, C (O) OH, halogen, R ^h , SR ^h , S (O) R ^h , S (O) ₂ R ^h , S (O) OR ^h , S (O ) ₂ OR ^h , OS (O) R ^h , OS (O) ₂ R ^h , OS (O) OR ^h , OS (O) ₂ OR ^h , OR ^h , NHR ^h , N (R ^h ) R ⁱ , ⁺ N (R ^h ) (R ⁱ ) R ^j , P (O) (OR ^h ) (OR ⁱ ), OP (O) (OR ^h ) (OR ⁱ ), SiR ^h R ⁱ R ^j , C (O) R ^h , C (O) OR ^h , C (O) N (R ^h ) R ⁱ , OC (O) R ^h , OC (O) OR ^h , OC (O) N (R ^h ) R ⁱ , N (R ^h ) C (O) R ⁱ , N (R ^h ) C (O) OR ⁱ , N (R ^h ) C (O) N (R ⁱ ) R ^j and a water-soluble group, where

R ^h , R ⁱ and R ^{j are} independently selected from H and optionally substituted (CH ₂ CH ₂ O) _ee CH ₂ CH ₂ X ¹³ R ^e1 , C _1-15 alkyl, C _1-15 heteroalkyl, C _3-15 cycloalkyl, C _1-15 heterocycloalkyl, C _5-15 aryl or C _1-15 heteroaryl, one or more optional substituents on R ^h , R ⁱ and / or R ^j are optionally a water soluble group, two or more of R ^h , R ⁱ and R ^j optionally connected by one or more bonds to form one or more optionally substituted carbocycles and / or heterocycles,

or R ⁸⁺ R ^{8 '} and / or R ⁹ + R ^9' and / or R ¹⁰⁺ R ^{10 '} and / or R ¹¹ + R ^11' and / or R ¹⁵ + R ^{15 '} and / or R ^15' + R ^{15 '''} and / or R ¹⁶ + R ^16' and / or R ²⁰ + R ^{20 '} and / or R ²¹ + R ^{21' are} independently selected from = O, = S, = NOR ^h1 , = C (R ^h1 ) R ^h2 and = NR ^h1 , R ^h1 and R ^{h2 are} independently selected from H and optionally substituted C _1-3 alkyl, two or more of R ⁸ , R ^{8 '} , R ⁹ , R ^9' , R ¹⁰ , R ^{10 '} , R ¹¹ , R ^11' , R ¹⁵ , R ^{15 '} , R ^15'' , R ^15''' , R ¹⁶ , R ^{16 '} , R ²⁰ , R ^20' , R ²¹ , R ^{21 '} , R ²² and R ²³ optionally connected by one or more bonds to form one or more optionally substituted carbocycles and / or heterocycles;

R ^8b and R ^9b are independently selected and have the same meanings as defined for R ⁸ , except that they cannot be linked to other substituents;

one of R ⁴ and R ^{4 '} and one of R ¹⁶ and R ^16' may optionally be connected by one or more bonds to form one or more optionally substituted carbocycles and / or heterocycles;

one of R ² , R ^{2 ′} , R ³ , and R ^{3 ′} and one of R ⁵ and R ^{5 ′} may optionally be linked by one or more bonds to form one or more optionally substituted carbocycles and / or heterocycles; and

a and b are independently 0 and 1.

In another aspect, the present invention relates to a compound of formula ( I ′ ) or ( II ′ ):

which is formed by rearrangement and simultaneous removal of HR ¹ from the corresponding compounds of formula ( I ) and ( II ), which are seco compounds (Fig. 1). These analogues containing a cyclopropyl ring are probably active species, which, apparently, are formed in vivo from the compounds of formulas ( I ) and ( II ) by this rearrangement.

In a more specific embodiment, the present invention relates to a compound of formula ( I ) or ( II ), as described above herein, where

a) the DB group does not contain the group DA1 , DA2 , DA1 ' or DA2' ; and

b) ring B in DB1 is a heterocycle; and

c) if X ³ in DB1 is - X ^3a and X ^3b - and ring B is aromatic, then two adjacent substituents on said ring B are combined to form an optionally substituted carbocycle or heterocycle fused to said ring B ; and

d) ifX ³ atDB2 represents -X ^3aandX ^3b-, and the ringBis an aromatic, then two adjacent substituents on the specified ringBcombined to form an optionally substituted heterocycle fused to said ringBoptionally substituted non-aromatic carbocycle fused to said ringBor substituted aromatic carbocycle which is fused to said ringB and to which is attached at least one substituent containing a hydroxy group, a primary amino group or a secondary amino group, where the primary or secondary amine is neither a ring atom in the aromatic ring system, nor is it part of an amide; and

e) if ring A in DB2 is a 6-membered aromatic ring, then the substituents on ring B are not combined to form a ring fused to ring B ; and

f) two adjacent substituents on ring A in DB8 are combined to form an optionally substituted carbocycle or heterocycle fused to said ring A to form a bicyclic group to which other rings are not fused; and

g) ring A in DB9, together with any other ring fused to said ring A, contain at least two ring heteroatoms.

In another embodiment, the present invention relates to a compound of formula ( I ) or ( II ) as described herein above, wherein at least one of the substituents R ¹ , R ⁵ , R ^{5 ′} , R ⁶ , R ^{6 ′} , R ⁷ , R ^{7 '} , R ¹⁴ , R ^14' , R ⁸ , R ^{8 '} , R ⁹ , R ^9' , R ¹⁰ , R ^{10 '} , R ¹¹ , R ^11' , R ¹⁵ , R ^{15 '} , R ^15`` , R ^{15 '''} , R ¹⁶ , R ^16' , R ²⁰ , R ^{20 '} , R ²¹ , R ^21' , R ²² and R ²³ contains the group X ¹⁴ (CH ₂ CH ₂ O) _ff CH ₂ CH ₂ X ¹⁴ , where ff is 1-1000, and each of X ^{14 is} independently selected from

which is attached to the attachment site of the indicated substituent either directly via a bond or through a group that is part of the same substituent that does not contain a disulfide, hydrazone, hydrazide, ester, natural amino acid or peptide containing at least one natural amino acid and where, if ring B in DB1 is an all-carbon ring, X ³ is O or NR ¹⁵ , X ⁴ is CH, X ³⁴ is C, then only the present compound of formula ( I ) or ( II ) is present about A group of ¹⁴ X (CH ₂ CH ₂ O) _ff CH ₂ CH ₂ and X ¹⁴ is part of said group R ^6, R ^7, R ^8, R ¹⁰ or R ¹⁵ when b = 1 and ff ≥5.

A compound of formula ( I ) or ( II ) or a conjugate thereof in which ff is greater than 1000 is also included in the scope of the present invention.

In another embodiment, the present invention relates to a compound of formula ( I ) or ( II ) as described herein above, wherein at least one of the substituents R ¹ , R ⁵ , R ^{5 ′} , R ⁶ , R ^{6 ′} , R ⁷ , R ^{7 '} , R ¹⁴ , R ^14' , R ⁸ , R ^{8 '} , R ⁹ , R ^9' , R ¹⁰ , R ^{10 '} , R ¹¹ , R ^11' , R ¹⁵ , R ^{15 '} , R ^{15 ″} , R ^{15 ″} , R ¹⁶ , R ^{16 ″} , R ²⁰ , R ^{20 ’} , R ²¹ , R ^21’ , R ²² and R ²³ contains a triazole group.

It should be noted that if -X ³- represents -X ^3a andX ^3b- in groupsDB1 andDB2then these groups are actually represented by the following structural formulas:

In another aspect, the present invention relates to conjugates of a compound of formula ( I ), ( II ), ( I ′ ) or ( II ′ ).

In another aspect, the present invention relates to a compound of formula ( III ):

,

,

or its pharmaceutically acceptable salt, hydrate or MES, where

V ² or absent or is a functional group;

everyoneL ², independently absent or is a binding groupV ² andL;

everyoneL, independently absent or is a binding groupL ² and one or moreV ^one and / orY;

everyoneV ^one, independently, absent or is a group that is cleaved or transformed under certain conditions, which can be cleaved or transformed during a chemical, photochemical, physical, biological or enzymatic process;

everyoneY, independently, absent or is a self-deleting intermediate system, which consists of 1 or more self-deleting intermediate groups and is associated withV ^one, not necessaryL, and one or moreZ;

each p and q is equal to a number corresponding to the degree of branching, and each independently is equal to a positive integer;

z is a positive integer equal to or less than the total number of points of attachment Z ;

everyoneZ, independently, is a compound of the formula (I), (II), (I ') or (II '), as defined herein above, where one or more ofX ^one, R⁵, R^5', R⁶, R^{6 '}, R⁷, R^{7 '}, R^fourteen, R^fourteen', R⁸, R^8', R⁹, R^9', R¹⁰, R^10', R^eleven, R^eleven', R^fifteen, R^fifteen', R^fifteen'', R^fifteen''', R¹⁶, R^16', R^twenty, R^twenty', R²¹, R^{21 '}, R²² and R²³ may optionally be further substituted or may represent a substituent of the formula (V):

where everyoneV ^{2 '},L ^{2 '} , L ',V ^one' , Y ',Z ', p ', q' and z 'have the same meaning as defined forV ²,L ²,L,V ^one,Y,Z, p, q and z, respectively, and independently selected, one or more substituents of the formula (V) are independently connected viaY 'from one or moreX ^one, R⁵, R^5', R⁶, R^{6 '}, R⁷, R^{7 '}, R^fourteen, R^fourteen', R⁸, R^8', R⁹, R^9', R¹⁰, R^10', R^eleven, R^eleven', R^fifteen, R^fifteen', R^fifteen'', R^fifteen''', R¹⁶, R^16', R^twenty, R^twenty', R²¹, R^{21 '}, R²², R²³ and / or with one or more atoms bearing these R substituents;

each Z is independently connected to Y either through X ¹ or through an atom in R ⁵ , R ^{5 '} , R ⁶ , R ^6' , R ⁷ , R ^{7 '} , R ¹⁴ , R ^14' , R ⁸ , R ^{8 '} , R ⁹ , R ^{9 '} , R ¹⁰ , R ^10' , R ¹¹ , R ^{11 '} , R ¹⁵ , R ^15' , R ^{15 ''} , R ^{15 '''} , R ¹⁶ , R ^16' , R ²⁰ , R ^{20 '} , R ²¹ , R ^21' , R ²² , R ²³ , or through an atom bearing any of these R substituents; and

at least V ² or V ^{1 is} present.

It should be noted that in the compound of the formula (III) must be presentV ² orV ^one. However, in one or more groups of the formula (V) that are optionally present inZ, everyoneV ^{2 '} andV ^one' may be absent or present independently.

In another aspect, the present invention relates to a compound of formula ( III ), where

V ² present and selected as a targeting fragment, and at least one group of the formula (V) that contains the groupV ^one' and contains either a groupV ^{2 '}eitherL ^{2 '}or groupL ^''which contains the groupX ^fourteen(CH₂CH₂O)_ggCH₂CH₂ X ^fourteenwhere gg is 3-1000 and each ofX ^fourteen independently selected from

or the same said group of formula ( V ) contains at least 2 groups X ¹⁴ CH ₂ CH ₂ OCH ₂ CH ₂ X ¹⁴ in which each of X ^{14 is} independently selected.

It should be noted that the individual groups X ¹⁴ in the groups —CH ₂ CH ₂ X ¹⁴ that may be present in the compound of formula ( III ) are independently selected.

It should also be noted that z does not represent the degree of polymerization; therefore, z does not indicate the number of Z groups connected to each other.

It should also be noted that if Y or Y 'is bonded to an atom bearing a specific substituent R instead of this substituent R itself, this means that this substituent R is absent if necessary to comply with the valency rules.

, то -CH₂CH₂ X ¹⁴ следует читать как -CH₂CHX ¹⁴.It should also be noted that if X ¹⁴ , for example, in -CH ₂ CH ₂ X ¹⁴ , represents

then -CH ₂ CH ₂ X ¹⁴ should be read as -CH ₂ CH X ¹⁴ .

The present invention also relates to a compound of formula (IV) :

,

,

or its pharmaceutically acceptable salt, hydrate or MES, where

RM is a reactive group, and L , V ¹ , Y , Z , p and z are as defined hereinabove, except that L is now linked to RM via one or more of V ¹ and / or Y , and V ¹ , Y and Z may contain protective groups, and one or more of the groups V ^{2 '} - L ^2' , optionally present in Z, as defined herein above, may optionally and independently be instead of RM ' , which is a reactive group , and where, if more than 1 reactive group is present in (IV) , some or all of the distinct groups are the same or different. These linker-agent conjugates of formula (IV) may or may not be considered as intermediates for compounds of formula ( III ).

In an additional aspect, the present invention relates to a compound of formula (IV) , wherein RM is a reactive group selected from carbamoyl halide, acyl halide, activated ester, anhydride, α-haloacetyl, α-haloacetamide, maleimide, isocyanate, isothiocyanate, disulfide, thiulfide hydrazine, hydrazide, sulfonyl chloride, aldehyde, methyl ketone, vinyl sulfone, halomethyl and methyl sulfonate, and where at least one group of formula ( V ), which is part Z , contains a group V ^{1 ′} and either holds a group V ^{2 '} , L ^2' or L ^' , which contains a group X ¹⁴ (CH ₂ CH ₂ O) _gg CH ₂ CH ₂ X ¹⁴ , where gg is 3-1000 and each of X ^{14 is} independently selected from

or the same said group of formula ( V ) contains at least 2 groups X ¹⁴ CH ₂ CH ₂ OCH ₂ CH ₂ X ¹⁴ , in which each of X ^{14 is} independently selected. These linker-agent conjugates of formula (IV) may or may not be considered as intermediates for compounds of formula ( III ).

The present invention relates to enantiomerically pure and / or diastereomerically pure compounds of the formulas ( I ) to (IV) , as well as to enantiomeric and / or diastereomeric mixtures of the compounds of the formulas ( I ) to (IV) . The present invention relates to pure compounds of formula ( I ) to (IV) , as well as to mixtures of isomers of compounds of formula ( I ) to (IV) .

The compounds of formulas ( I ) and ( II ) and their conjugates are novel duocarmycin derivatives, which preferably have new DNA binding fragments and / or preferably heteroatoms at selected positions in the DNA binding fragment or in substituents in the DNA binding or DNA alkylating fragment or in one or more cleavable linkers attached to a compound of formula ( I ) or ( II ). These modifications are obtained to improve the pharmacological properties and cytotoxic activity compared with duocarmycin derivatives known from the prior art.

In one embodiment, the compound of formula ( I ) or ( II ) contains a new DNA binding fragment. Without being bound by any theory, it is contemplated that these new DNA-binding fragments can contribute to the cytotoxic activity of compounds of formula ( I ) and ( II ) by binding to DNA in a manner similar to DNA-binding fragments in CC-1065 analogues known from the prior art. technicians. New DNA binding agents may be more water soluble, may have increased binding affinity and / or may be more easily metabolized, for example, in the liver, with the formation of compounds of formulas ( I ) and ( II ) with improved pharmacological properties, for example, enhanced therapeutic index, relative to similar compounds known from the prior art.

In another embodiment, the compound of formula ( I ) or ( II ) contains a triazole group. Without being bound by any theory, it is contemplated that this heteroaromatic group can be introduced into the molecule so that it promotes the binding of the compound of formula ( I ) or ( II ) to the DNA of the target cell, thereby improving the activity of the compound. Although a similar effect can be achieved using another (hetero) aromatic group, for example, a phenyl ring, the triazole group has the additional advantage that it is a relatively polar group (relative to other (hetero) aromatic groups), which can lead to improving pharmacological properties (e.g., water solubility, hydrophilicity, aggregation parameters) of compounds of formulas ( I ) and ( II ) and their conjugates.

In another embodiment, the compound of formula ( I ) or ( II ) contains an oligoethylene glycol or polyethylene glycol group or a derivative thereof. The specified group oligoethylene glycol or polyethylene glycol can be either branched or linear. Without being bound by any theory, it is contemplated that this group may be introduced into a compound of formula ( I ) or ( II ) to improve, for example, the physicochemical, biophysical, pharmacodynamic and / or pharmacokinetic properties of the compound, for example, water solubility and aggregation parameters. Furthermore, due to the hydrophilicity of the oligoethylene glycol or polyethylene glycol group, the compound of formula ( I ) or ( II ), for example, may be more cytotoxic to tumor cells that are resistant to many drugs, since the compound is a poor substrate for efflux pumps. If the compound of formula ( I ) or ( II ) is included in the conjugate, it is possible that the oligoethylene glycol or polyethylene glycol group is located between the progroup, i.e. a group attached to the compound of formula ( I ) or ( II ) to change its properties and which (partially) is removed in vivo from the specified compound of formula ( I ) or ( II ), and the remainder of the compounds of formula ( I ) or ( II ) or that is located in a position slightly opposite to the point of attachment of the progroup, thus placing the remainder of the compounds of formula ( I ) or ( II ) between the progroup and the oligoethylene glycol or polyethylene glycol group. The latter condition may be advantageous in the sense that the hydrophobic (aromatic) structure of the core of the compound of formula ( I ) or ( II ) is more protected from adverse interactions with its environment, for example, the aqueous environment, thus, for example, reducing the amount of aggregation formation .

In another embodiment, the present invention relates to a conjugate of a compound of formula ( I ) or ( II ) in accordance with one of the above embodiments and its derivative. These conjugates contain one or more progroups.

In another embodiment, the conjugate of a compound of formula ( I ) or ( II ) contains at least two groups, of which the first group is an in vivo cleavable progroup that contains an oligoethylene glycol or polyethylene glycol group or derivative thereof, and the second group contains at least least targeting group. Such a conjugate has a relatively hydrophobic core structure of a compound of formula ( I ) or ( II ) or a derivative thereof located between a guide group and a group containing oligoethylene glycol or polyethylene glycol, thereby protecting the core structure from possible adverse interactions with its environment.

The compounds of formula ( I ) and (II ) are suitable for use in drug delivery, including drug targeting and controlled release, using the compounds of formulas ( III ) and (IV) .

BRIEF DESCRIPTION OF THE DRAWINGS

In FIG. 1 shows a rearrangement of a seco compound for a cyclopropyl-containing compound.

In FIG. 2 shows the synthesis of alkylating groups 4a - 4k .

In FIG. 3 shows the synthesis of alkylating groups 8a - 8d .

In FIG. 4 shows the synthesis of alkylating groups 12 and 16 .

In FIG. 5 depicts the synthesis of duocarmycins containing 7-substituted indolysin.

In FIG. 6 depicts the synthesis of duocarmycins containing 6-substituted indolysin.

In FIG. 7 shows the synthesis of compound 110 .

In FIG. Figure 8 shows the synthesis of duocarmycins containing 7-azabenzofuran.

In FIG. 9 shows the synthesis of compound 112 .

In FIG. 10 shows the synthesis of the linker-agent conjugate 114 .

In FIG. 11 shows the synthesis of a linker-agent conjugate 115 .

In FIG. 12 depicts linker-agent 116 conjugate synthesis.

In FIG. 13 shows linker-agent conjugates 117, 118, 119 and 120 .

DESCRIPTION OF THE INVENTION

The following detailed description is provided for a more complete understanding of the invention.

Definitions

Unless otherwise specified, all technical and scientific terms used in this document have the same meanings as defined for the ordinary understanding of a person skilled in the art.

As used herein, the term “antibody” refers to a full-length immunoglobulin molecule, an immunologically active part of a full-length immunoglobulin molecule, or a derivative of a full-length immunoglobulin molecule or its active part, i.e. a molecule that contains an antigen binding site that immunospecifically binds an antigen of a target of interest or a part thereof, such targets include, but are not limited to, tumor cells. The immunoglobulin can be of any type (e.g., IgG, IgE, IgM, IgD, IgA or IgY), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1 or IgA2) or a subclass. The immunoglobulin or its derivative or active part can be isolated from individuals of any biological species, for example, humans, rodents (e.g., mice, rats or hamsters), donkey, sheep, rabbit, goat, guinea pig, camel, horse, cow or chicken, but preferably a human, mouse or rabbit, or isolated from more than one species. Antibodies used in the invention include, but are not limited to, monoclonal, polyclonal, bispecific, multispecific, human, humanized, chimeric and engineered antibodies, single chain antibodies, Fv fragments, Fd fragments, Fab fragments, F (ab ') fragments, F (ab ') ₂ fragments, dAb-fragments, fragments derived from the Fab-expression library, anti-idiotypic antibodies, CDR-dedicated and epitope-binding fragments of any of the foregoing antibodies immunospecifically bind to and representing Theres antigen.

The term “leaving group” refers to a group that may be substituted by another group in a substitution reaction. Such leaving groups are well known in the art and examples include, but are not limited to, a halide (fluoride, chloride, bromide and iodide), azide, sulfonate (e.g., optionally substituted C _1-6 alkanesulfonate, such as methanesulfonate and trifluoromethanesulfonate, or optionally substituted C _7-12 alkylbenzenesulfonate, such as p- toluenesulfonate), succinimide N -oxide, p-nitrophenoxide, pentafluorophenoxide, tetrafluorophenoxide, carboxylate, aminocarboxylate (carbamate) and alkoxycarboxylate (carbonate). For substitutions at the saturated carbon atom, halides and sulfonates are preferred leaving groups. For substitutions at the carbonyl carbon atom, a halide, succinimide- N -oxide, p-nitrophenoxide, pentafluorophenoxide, tetrafluorophenoxide, carboxylate or alkoxycarboxylate (carbonate) can, for example, be used as a leaving group. The term “leaving group” also refers to a group that is cleaved as a result of an elimination reaction, for example, by an electronic cascade reaction or a spirocyclization reaction. In this case, a halide, sulfonate, azide, aminocarboxylate (carbamate) or alkoxycarboxylate (carbonate) can, for example, be used as a leaving group. Thus, a substance or its derivative released from the conjugate through (diverse) self-removal is defined as a leaving group in accordance with this definition.

The term "activated ester" refers to a functional group in which the alkoxy group in the ester group is an easily removable group. Examples of such alkoxy groups include, but are not limited to, succinimide N -oxide, p-nitrophenoxide, pentafluorophenoxide, tetrafluorophenoxide, 1-hydroxybenzotriazole and 1-hydroxy-7-azabenzotriazole, and groups with a similar removal ability. Unsubstituted alkyl alkoxy groups such as methoxy, ethoxy, isopropoxy and tert-butoxy cannot be considered as readily removable groups, and methyl, ethyl, isopropyl and tert-butyl esters are thus not considered as active esters.

The term "reactive group" as used herein refers to a functional group that can interact with another functional group under relatively mild conditions and without the need for preliminary functionalization of the reaction group. The interaction between the reaction group and said other functional group will only require the use of some heating, pressure, catalyst, acid and / or base. Examples of reactive groups include, but are not limited to, carbamoyl halide, acyl halide, activated ester, anhydride, α-haloacetyl, α-haloacetamide, maleimide, isocyanate, isothiocyanate, disulfide, thiol, hydrazine, hydrazide, sulfonyl chloride, sulfonyl chloride, sulfonyl chloride, sulfonyl chloride , halomethyl and methyl sulfonate.

The term "progroup" refers to a group that binds to a compound of formula ( I ) or ( II ) to change its properties and which (partially) is removed in vivo from the specified compound of formula ( I ) or ( II ).

The term “water soluble group” refers to a functional group that is highly soluble in aqueous media and provides improved water solubility to the compound to which it is attached. Examples of water-soluble groups include, but are not limited to, polyalcohols, straight chain saccharides or cyclic saccharides, primary, secondary, tertiary or quaternary amines and polyamines, sulfate groups, sulfonate groups, sulfate groups, carboxylate groups, phosphate groups, phosphonate groups, phosphate groups groups, ascorbate groups, glycols, including polyethylene glycols, and polyethers. Preferred water-soluble groups are primary, secondary, tertiary and quaternary amines, carboxylates, phosphates, - (CH ₂ CH ₂ O) _yy CH ₂ CH ₂ X ¹⁷ R ^yy , - (CH ₂ CH ₂ O) _yy CH ₂ CH ₂ X ¹⁷ -, - X ¹⁷ (CH ₂ CH ₂ O) _yy CH ₂ CH ₂ -, glycol, oligoethylene glycol and polyethylene glycol, where yy is 1-1000, X ^{17 is} selected from O, S and NR ^zz , and R ^zz and R ^{yy are} independently selected from H and C _1-3 alkyl.

The term "substituted" when used as an adjective to the term "alkyl", "heteroalkyl", "cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl" or the like, indicates that the specified "alkyl", " a heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group contains one or more substituents (introduced by hydrogen substitution). Examples of substituents include, but are not limited to, OH, = O, = S, = NR ^k , = N-OR ^k , SH, NH ₂ , NO ₂ , NO, N ₃ , CF ₃ , CN, OCN, SCN, NCO , NCS, C (O) NH ₂ , C (O) H, C (O) OH, halogen, R ^k , SR ^k , S (O) R ^k , S (O) OR ^k , S (O) ₂ R ^k , S (O) ₂ OR ^k , OS (O) R ^k , OS (O) OR ^k , OS (O) ₂ R ^k , OS (O) ₂ OR ^k , S (O) N (R ^k ) R ^l , OS (O) N (R ^k ) R ^l , S (O) ₂ N (R ^k ) R ^l , OS (O) ₂ N (R ^k ) R ^l , OP (O) (OR ^k ) (OR ^l ), P (O) (OR ^k ) (OR ^l ), OR ^k , NHR ^k , N (R ^k ) R ^l , ⁺ N (R ^k ) (R ^l ) R ^m , Si (R ^k ) (R ^l ) (R ^m ), C (O) R ^k , C (O) OR ^k , C (O) N (R ^k ) R ^l , OC (O) R ^k , OC (O) OR ^k , OC (O ) N (R ^k ) R ^l , N (R ^k ) C (O) R ^l , N (R ^k ) C (O) OR ^l , N (R ^k ) C (O) N (R ^l ) R ^m , a water-soluble group and the thio derivatives of these substituents, and protonated, having a charge, and deprotonated forms of any of these substituents, where R ^k , R ^l and R ^{m are} independently selected s of H and optionally substituted - (CH ₂ CH ₂ O) _yy CH ₂ CH ₂ X ¹⁷ R ^yy , C _1-15 alkyl, C _1-15 heteroalkyl, C _3-15 cycloalkyl, C _1-15 heterocycloalkyl, C _{5 -15} aryl or C _1-15 heteroaryl, or combinations thereof, where yy is 1-1000, X ^{17 is} independently selected from O, S and NR ^zz , and R ^zz and R ^{yy are} independently selected from H and C _1-3 alkyl, two or more R ^k , R ^l and R ^{m are} optionally joined by one or more bonds to form one or more optionally substituted carbocycles and / or heterocycles. In the case where more than one substituent is present, each substituent is independently selected. Two or more substituents can be linked to each other by replacing one or more hydrogen atoms in each substituent with one or more bonds, which can be single, double or triple bonds, or, if resonance structures are possible, the multiplicity of bonds in these bonds may differ in two or more of these resonant structures. Thus, two substituents can be linked to form one or more rings.

When substituents can be “linked by one or more bonds to one or more optionally substituted carbocycles and / or heterocycles”, this means that the substituents can be linked to each other by replacing one or more hydrogen atoms in each substituent with one or more bonds.

As used herein, the term “aryl” refers to a carbocyclic aromatic substituent containing from 5 to 24 ring carbon atoms, which may or may not have a charge and which may consist of one ring or two or more condensed rings. Examples of aryl groups include, but are not limited to, phenyl, naphthyl and anthracenyl.

As used herein, the term “heteroaryl” refers to a heterocyclic aromatic substituent containing from 1 to 24 ring carbon atoms and at least one ring heteroatom, for example, oxygen, nitrogen, sulfur, silicon or phosphorus, where nitrogen and sulfur can be optionally oxidized, and nitrogen may optionally be quaternized, which consists of one ring or two or more condensed rings. Hetero atoms can be directly connected to each other. Examples of heteroaryl groups include, but are not limited to, pyridinyl, pyrimidyl, furanyl, pyrrolyl, triazolyl, pyrazolyl, pyrazinyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, thienyl, indolyl, benzofuranyl, benzimidazolyl, benzothiazolazolazole, pu quinoxalinyl, isoquinolyl and quinolyl. In one embodiment, the heteroaryl group contains from 1 to 4 heteroatoms. It should be noted that the expression “C ₁ heteroaryl group” means that there is only one carbon atom in the ring system of the heteroaromatic group (carbon atoms in optional substituents are thus not taken into account). An example of such a heteroaromatic group is a tetrazolyl group.

The aryl and heteroaryl groups also include ring systems in which one or more non-aromatic rings are fused to an aryl or heteroaryl ring or ring system.

As used herein, the term “alkyl” refers to a straight or branched chain saturated or unsaturated alkyl substituent. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, octyl, decyl, isopropyl, sec-butyl, isobutyl, tert-butyl , isopentyl, 2-methylbutyl, vinyl, allyl, 1- butenyl, 2-butenyl, isobutenyl, 1-pentenyl, 2-pentenyl and 1-butynyl.

As used herein, the term “heteroalkyl” refers to a straight or branched chain saturated or unsaturated hydrocarbon substituent in which at least one carbon atom is replaced by a hetero atom, for example, oxygen, nitrogen, sulfur, silicon or phosphorus, where nitrogen and sulfur may optionally be oxidized and nitrogen may optionally be quaternized. Hetero atoms can be directly linked to each other. Examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butyloxy, tert- butyloxy, methoxymethyl, ethyloxymethyl, methyloxyethyl, ethyloxyethyl, methylaminomethyl, dimethylaminomethyl, methylaminoethyl, dimethylaminoethyl, methylthiomethyl, ethyl, ethyl.

As used herein, the term “cycloalkyl” refers to a saturated or unsaturated non-aromatic cyclic alkyl substituent that consists of one ring or two or more fused rings. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, 1,3-cyclohexadienyl, decalinyl and 1,4-cyclohexadienyl.

As used herein, the term “heterocycloalkyl” refers to a saturated or unsaturated non-aromatic cyclic hydrocarbon substituent, which consists of one ring or two or more condensed rings, where at least one carbon atom in one of the rings is replaced by a heteroatom, for example, oxygen, nitrogen, sulfur, silicon or phosphorus, where nitrogen and sulfur may optionally be oxidized and nitrogen may optionally be quaternized. Hetero atoms can be directly linked to each other. Examples include, but are not limited to, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, 1,4-dioxanyl, decahydroquinolinyl, piperazinyl, oxazolidinyl and morpholinyl. It should be noted that the expression “C ₁ heterocycloalkyl group” means that there is only one carbon atom in the ring system of the heterocycloalkane (carbon atoms in optional substituents are thus not taken into account). An example of such a group is a dioxiranyl group.

The number of carbon atoms that may contain "alkyl", "heteroalkyl", "cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl" and the like is indicated by the designation preceding these terms, i.e. C _1-10 alkyl means that said alkyl may contain from one to ten carbon atoms (carbon atoms in the optional substituents attached to this alkyl are not taken into account).

The term “carbocycle” as used herein refers to a saturated or unsaturated cycloalkane or arene group, wherein the terms “cycloalkane” and “arenes” are defined as the starting groups of the substituents “cycloalkyl” and “aryl”, respectively, as defined hereinabove.

The term “heterocycle” as used herein refers to a saturated or unsaturated heterocycloalkane or heteroarene moiety, where the terms “heterocycloalkane” and “heteroarene” are defined as the parent moieties of the substituents “heterocycloalkyl” and “heteroaryl, respectively, as defined hereinabove.

The termination of "-ylene" as opposed to "-yl", for example, in the term "alkylene" in comparison with "alkyl" indicates that the specified, for example, "alkylene" is a divalent (or polyvalent) group associated with one or more other groups by at least one or more double bonds, or two or more single bonds, as opposed to being a monovalent group, linked to one group by one single bond in the specified, for example, "alkyl". As used herein, the term “alkylene” thus refers to a straight or branched chain saturated or unsaturated alkylene group; the term “heteroalkylene” refers to a straight or branched chain saturated or unsaturated alkylene group in which at least one carbon is replaced by a heteroatom; as used herein, the term “arylene” refers to a carbocyclic aromatic group that consists of one ring or two or more fused rings; as used herein, the term “heteroarylene” refers to a carbocyclic aromatic group that consists of one ring or two or more fused rings, where at least one carbon atom in one of the rings is replaced by a heteroatom; as used herein, the term “cycloalkylene” refers to a saturated or unsaturated non-aromatic cyclic alkylene group that consists of one ring or two or more fused rings; As used herein, the term “heterocycloalkylene” refers to a saturated or unsaturated non-aromatic cyclic alkylene group that consists of one ring or two or more fused rings, where at least one carbon atom in one of the rings is replaced by a heteroatom. Examples of divalent groups include examples given for monovalent groups described hereinabove in which one hydrogen atom is removed.

The prefix "poly" to "polyalkylene", "polyheteroalkylene", "polyarylene", "polyheteroarylene", polycycloalkylene "," polyheterocycloalkylene "and the like shows that two or more of such" -ylene "groups, for example alkylene groups, are linked together with the formation of a branched or unbranched polyvalent group containing two or more points of attachment of adjacent groups.Likewise, the prefix "oligo", for example, in oligoethylene glycol, shows that two or more ethylene glycol groups are linked to each other with the formation of branched or undeveloped The difference between oligo and poly prefixes is that the oligo prefix is more often used to refer to a relatively small number of repeating units, while the poly prefix usually refers to a relatively large number of repeating units. links.

Some compounds of the invention have chiral centers and / or double bonds, and / or may have tautomers or atropisomers; tautomeric, enantiomeric, diastereomeric, atropisomeric and geometric mixtures of two or more isomers in any combination, as well as individual isomers (including tautomers and atropisomers) are included in the scope of the present invention. Each time the term "isomer" is used, it refers to the atropisomeric, tautomeric, enantiomeric, diastereomeric and / or geometric isomers, or to a mixture of two or more of these isomers, unless otherwise indicated in the context.

The term "peptidomimetic" refers to a group or fragment that has a structure different from the general chemical structure of an amino acid or peptide, but functions similarly to a natural amino acid or peptide. Thus, a peptidomimetic is an amino acid expression or peptide expression.

The term "unnatural amino acid" refers to the D-stereoisomer of a natural amino acid.

The term “bond” as used herein refers to a covalent bond between two atoms and may refer to a single bond, double bond or triple bond, or, if resonant structures are possible, the bond multiplicity in said bonds may differ in two or more of these resonant structures. For example, if the bond is part of an aromatic ring, the bond may be a single bond in one resonant structure and a double bond in another resonant structure. If it is stated that there is a “double bond” or “triple bond” between two atoms, this double or triple bond can be localized, but it can also be that this double or triple bond is delocalized, which means that only in one or more resonance structures, a double or triple bond is actually present between two atoms, despite the fact that the multiplicity of the bond may be different in one or more other resonant structures. At the same time, bonds marked as a single bond in one resonant structure can be double bonds in another resonant structure.

The compounds of the invention may also contain a non-naturally occurring amount of atomic isotopes in one or more atoms forming such compounds. All variants of the isotopes of the compounds of the present invention, radioactive or non-radioactive, are included in the scope of the present invention.

As used herein, the term “pharmaceutically active salt” refers to a pharmaceutically acceptable organic or inorganic salt of a compound of the invention. For compounds containing one or more basic groups, for example, an amino group, acid addition salts can be prepared. For compounds containing one or more acid groups, for example, a carboxyl group, base addition salts can be obtained. For compounds containing both acidic and basic groups, in addition, zwitterions in the form of salts can be obtained. When a compound of the invention contains more than one charged atom or group, a number of (different) counterions may be present.

The term “pharmaceutically acceptable solvate” refers to the product of a compound of one or more solvent molecules with a compound of the invention. Examples of solvents forming pharmaceutically acceptable solvates include, but are not limited to, water, isopropyl alcohol, ethanol, methanol, DMSO, ethyl acetate, and acetic acid. When using water as a solvate, the term "hydrate" may be used.

The term "conjugate" hereinafter refers to a compound of formula ( III ) or a conjugate of a compound of formula ( I ) or ( II ) or a derivative thereof, unless otherwise indicated in the context.

The term "linker-agent conjugate" hereinafter refers to the compound of formula (IV) , unless otherwise indicated in the context.

The term "agent" hereinafter refers to a compound of formula ( I ), ( II ), ( I ' ) or ( II' ), unless otherwise indicated in the context.

The term “core” or “core structure” of a fragment, for example, a DNA binding or DNA alkylating fragment, refers to a structure that is retained when all R substituents are removed from the formula representing the indicated group.

The term “targeting fragment” refers to any fragment that specifically binds or reactively binds, or forms a specific complex with a fragment that is either present in relative excess at the target site, or is present near the target site, on the target cell, in the cell- target or near the target cell, or in (near) the target tissue or organ, for example, a receptor, receptor complex, substrate, antigenic determinant or other receptive fragment, or which can target the conjugate to the target site by means of their mechanisms in accordance with its nature, for example by EPR effect. Examples of a guide fragment include, but are not limited to, an aptamer, antibody, or antibody fragment or derivative, polymer, dendrimer, lectin, biological response modifier, enzyme, vitamin, growth factor, steroid, sugar residue, oligosaccharide residue, protein carrier and hormone, or any combination of them.

The expression “group that improves the pharmacological properties of a compound” refers to a group that changes the pharmacological properties (eg, pharmacodynamic, pharmacokinetic, physico-chemical and biopharmaceutical properties) of a compound of the present invention so that an improved therapeutic effect can be obtained. A group may, for example, increase water solubility, circulation rate, therapeutic index, or decrease immunogenicity.

The term “linking group” refers to a structural element of a compound that binds one structural element of said compound to one or more other structural elements of the same specified compound.

The expression “a number representing the degree of branching” is used to denote in such a way that the subscript next to the closing bracket indicates how many links of the group inside the brackets are directly attached, each to the group to the left of the corresponding opening bracket. For example, in A- (B) _{b, the} index b, which is a number representing the degree of branching, shows that b links of B, each, are directly attached to A. This means that when b is 2, the formula has the form BAB.

The expression "a number representing the degree of polymerization" is used to denote in such a way that the lower index next to the closing bracket indicates how many links of the group inside the brackets are connected to each other. For example, in A- (B) _{b, the} index b, which is a number representing the degree of polymerization, shows that when b is 2, the formula is reduced to ABB.

The term “one-way spacer” refers to a self-destructible spacer that can release one group upon self-decay.

The term "multiple-release spacer" refers to a self-destructible spacer that can release two or more groups upon (repeated) self-decay.

The term "electronic cascade spacer" refers to a self-destructible spacer, either branched or unbranched, which can self-destruct by one or more elimination reactions with a 1.2 + 2 n electron cascade ( n ≥1).

The term "spacer with ω-aminoaminocarbonyl cyclization" refers to a self-destructible spacer that can be destroyed by a cyclization reaction to form a cyclic urea derivative.

The term "spacer system" refers to a single self-destructible spacer fragment or to two or more similar or different self-destructible spacer fragments linked together. The spacer system may be branched or unbranched and contain one or more attachment sites for Z, as well as V ¹ and optionally L.

In this document and its claims, the verbs “include”, “have”, “contain” and their conjugations are used in their non-limiting sense, meaning that elements that are “included”, “exist” or “contain” are included in the scope of the invention However, elements that are not specifically indicated are not excluded.

To identify structural elements in general structures throughout the description and in the claims, letter designations are used. Some of these notations, such as C, N, O, P, K, B, F, S, U, V, W, I, and Y, may erroneously denote an atom. To avoid confusion, whenever these letters do not represent an atom, they are shown in bold.

When there is one or more adjectives and / or adjective phrases related to a noun that is a) first in the list of nouns or b) anywhere in the middle of the list of nouns, and the indicated noun and adjective together are preceded by the word "and" or "or" , adjectives apply not only to the indicated noun, but to all other nouns individually, unless the context indicates otherwise. This means, for example, that the expression "optionally substituted C _1-4 alkyl, C _1-4 heteroalkyl, C _3-7 cycloalkyl or C _1-7 heterocycloalkyl" should read "optionally substituted C _1-4 alkyl, optionally substituted C _{1 -4} heteroalkyl, optionally substituted C _3-7 cycloalkyl or optionally substituted C _1-7 heterocycloalkyl, and the expression "C _1-4 alkyl, C _1-4 heteroalkyl and optionally substituted C _3-7 cycloalkyl, C _5-8 aryl or C _1-7 heterocycloalkyl "should be read as" C _1-4 alkyl, C _1-4 heteroalkyl, and optionally substituted C _3-7 cycloalkyl, optionally after eschenny C _5-8 aryl, or optionally substituted C _1-7 heterocycloalkyl ".

Throughout the description and in the claims of the present invention, molecular structures or parts thereof are described. Typically, in such figures, compounds between atoms are shown by lines, in some cases, to indicate stereochemistry, in bold or broken or wavy lines. Usually the line ends “in space” (the “free” end), that is, at one end that does not have another line or a specific atom associated with it, it represents a CH ₃ group. This corresponds to the drawings representing the compounds of the present invention. For these structures representing the structural element of the compounds of the present invention, a line ending “in space” may indicate the attachment position of another structural element of the compound. This is indicated by a wavy line perpendicular to and intersecting the line with the “free” end.

In addition, structures or parts of them were drawn under the assumption that the structures are read from left to right, meaning that, for example, in the compounds of formulas ( III ), V ² (if present) is located on the left side, and Z is located on the right side of such structures or parts thereof, unless the context indicates otherwise.

The following abbreviations are used herein, which have the indicated meanings: Ac: acetyl; AIBN: 2,2′-azobis (2-methylpropionitrile); Bn: benzyl; Boc: tert- butyloxycarbonyl; CBI: 1,2,9,9a-tetrahydrocyclopropa [c] benz [e] indol-4-one; DABCO: 1,4-diazabicyclo [2.2.2] octane; DBU: 1,8-diazabicyclo [5.4.0] undec-7-ene; DCC: N , N ' -dicyclohexylcarbodiimide; DCM: dichloromethane; DMA: N , N- dimethylacetamide; DMAP: 4-dimethylaminopyridine; DMF: N , N- dimethylformamide; DiPEA: N , N- diisopropylethylamine; DPPA: diphenylphosphorylazide; EDAC: 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide; EtOAc: ethyl acetate; Fmoc: 9-fluorenylmethyloxycarbonyl; HATU: 2- (1H-7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyl uronium methanamino hexafluorophosphate; HOBt: N- hydroxybenzotriazole; PNPCl: p- nitrophenyl chloroformate; ppm: parts per million; py: pyridine; TEA: triethylamine; TFA: trifluoroacetic acid; TFAA: trifluoroacetic anhydride; THF: tetrahydrofuran; TsOH: p- toluenesulfonic acid; TsCl: p- toluenesulfonyl chloride; and TTMSS: tris (trimethylsilyl) silane.

Agents, conjugates, linker-agent and conjugates

The present invention relates to new analogues of the DNA-alkylating agent CC-1065. The agents of the present invention are believed to be used to treat a disease that is characterized by unwanted (cell) proliferation. For example, the agent of the present invention can be used in the treatment of a tumor, malignant tumor, autoimmune disease or infectious disease.

The conjugates of the present invention in one aspect, which is believed to be applicable for targeting the agents of formula (I) and (II) to a specific target site, where the conjugate can be converted into one or more agents or induced to convert to one or more of these agents. In addition, the present invention may find application in the (non-specific) controlled release of one or more of these agents from a conjugate, for example, to improve physicochemical, biopharmaceutical, pharmacodynamic and / or pharmacokinetic properties.

The compounds of formulas ( I ) and ( II ) and their conjugates are novel duocarmycin derivatives which preferably have new DNA binding fragments and / or preferably have heteroatoms at selected positions in the DNA binding fragment or in substituents on the DNA binding or DNA- an alkylating moiety, or in one or more cleavable linkers attached to a compound of formula (I) or (II) . These modifications are obtained to improve the pharmacological properties and cytotoxic activity compared with duocarmycin derivatives known from the prior art.

In one embodiment, the compound of formula ( I ) or ( II ) contains a new DNA binding fragment. Without being bound by any theory, these new DNA binding fragments can contribute to the cytotoxic activity of compounds ( I ) and ( II ) by binding to DNA similarly to the DNA binding fragments in CC-1065 analogues known from the prior art. New DNA-binding fragments may be more water soluble, may have increased binding affinity and / or may be more easily metabolized, for example, in the liver, with the formation of compounds of formula ( I ) and ( II ) with improved pharmacological properties, for example, higher therapeutic index, relative to similar compounds known from the prior art.

In another embodiment, the compound of formula ( I ) or ( II ) contains a triazole group. Without being bound to any theory, this heteroaromatic group can be introduced into the molecule so that it promotes the binding of the compound of formula ( I ) or ( II ) to the DNA of the target cell, thereby improving the activity of the compound. Although a similar effect can be achieved using another (hetero) aromatic group, for example, a phenyl ring, the triazole group has the additional advantage that it is a relatively polar group (relative to other (hetero) aromatic groups), which can lead to improving pharmacological properties (e.g., water solubility, hydrophilicity, aggregation parameters) of compounds of formulas ( I ) and ( II ) and their conjugates.

In another embodiment, the compound of formula ( I ) or ( II ) contains an oligoethylene glycol or polyethylene glycol group or a derivative thereof. Said oligoethylene glycol or polyethylene glycol group may be either branched or linear. Without being bound by any theory, this group can be introduced into the compound of formula ( I ) or ( II ) to improve, for example, the physicochemical, biophysical, pharmacodynamic and / or pharmacokinetic properties of the compound, for example, water solubility and aggregation parameters. Furthermore, due to the hydrophilicity of the oligoethylene glycol or polyethylene glycol fragment, the compound of formula ( I ) or ( II ), for example, may be more cytotoxic to tumor cells that are resistant to many drugs, since the compound is a poor substrate for efflux pumps. If a compound of formula ( I ) or ( II ) is included in the conjugate, it is possible that an oligoethylene glycol or polyethylene glycol group is located between the progroup, i.e. a group attached to the compound of formula ( I ) or ( II ) to change its properties and which (partially) is removed in vivo from the specified compound of formula ( I ) or ( II ), and the remainder of the compounds of formula ( I ) or ( II ) or that is located in a position slightly opposite to the point of attachment of the progroup, thus placing the remainder of the compounds of formula ( I ) or ( II ) between the progroup and oligoethylene glycol or polyethylene glycol group. The latter condition may be advantageous in the sense that the hydrophobic (aromatic) structure of the core of the compound of formula ( I ) or ( II ) is more protected from adverse interactions with its environment, for example, the aqueous environment, thus, for example, reducing the amount of aggregation formation .

In another embodiment, the present invention relates to a conjugate of a compound of formula ( I ) or ( II ) and its derivatives. These conjugates contain one or more progroups.

In another embodiment, the conjugate of the compound of formula ( I ) or ( II ) contains at least two progroups, of which the first progroup is an in vivo cleavable progroup that contains an oligoethylene glycol or polyethylene glycol group or derivative thereof, and the second group contains at least least targeting fragment. Such a conjugate has a relatively hydrophobic core structure of a compound of formula ( I ) or ( II ) or a derivative thereof located between a guide progroup and a progroup containing oligoethylene glycol or polyethylene glycol, thereby protecting the core structure from possible adverse interactions of its environment.

Compounds of formula ( I ) and (II ) are suitable for use in drug delivery, including targeting and controlled release of a drug, using compounds of formula ( III ) and (IV) .

Agents

In one aspect, the present invention relates to a compound of formula ( I ) or ( II ):

,

,

or its pharmaceutically acceptable salt, hydrate or MES, where

DB is a DNA binding group and is selected from the group consisting of

,

,

R ¹ represents a leaving group;

R ² , R ^{2 '} , R ³ , R ^3' , R ⁴ , R ^{4 '} , R ¹² and R ^{19 are} independently selected from H, OH, SH, NH ₂ , N ₃ , NO ₂ , NO, CF ₃ , CN , C (O) NH ₂ , C (O) H, C (O) OH, halogen, R ^a , SR ^a , S (O) R ^a , S (O) ₂ R ^a , S (O) OR ^a , S (O) ₂ OR ^a , OS (O) R ^a , OS (O) ₂ R ^a , OS (O) OR ^a , OS (O) ₂ OR ^a , OR ^a , NHR ^a , N (R ^a ) R ^b , ⁺ N (R ^a ) (R ^b ) R ^c , P (O) (OR ^a ) (OR ^b ), OP (O) (OR ^a ) (OR ^b ), SiR ^a R ^b R ^c , C ( O) R ^a , C (O) OR ^a , C (O) N (R ^a ) R ^b , OC (O) R ^a , OC (O) OR ^a , OC (O) N (Ra) R ^b , N (R ^a ) C (O) R ^b , N (R ^a ) C (O) OR ^b and N (R ^a ) C (O) N (R ^b ) R ^c , where

R ^a , R ^b and R ^{c are} independently selected from H and optionally substituted C _1-3 alkyl or C _1-3 heteroalkyl,

or R ³ + R ^{3 '} and / or R ⁴ + R ^{4' are} independently selected from = O, = S, = NOR ¹⁸ , = C (R ¹⁸ ) R ^{18 '} and = NR ¹⁸ , R ¹⁸ and R ^18' independently selected from H and optionally substituted C _1-3 alkyl, two or more of R ² , R ^{2 '} , R ³ , R ^3' , R ⁴ , R ^{4 '} and R ^{12 are} optionally joined by one or more bonds to form one or more optionally substituted carbocycles and / or heterocycles;

X ² selected from O, C (R^fourteen) (R^fourteen') and NR^fourteen'where R^fourteen and R^fourteen' have the same meanings as defined for R⁷ and independently selected, or R^fourteen' and R^{7 '} are absent, which gives a double bond between atoms carrying R^{7 '} and R^fourteen';

R ⁵ , R ^{5 '} , R ⁶ , R ^6' , R ⁷ and R ^{7 'are} independently selected from H, OH, SH, NH ₂ , N ₃ , NO ₂ , NO, CF ₃ , CN, C (O) NH ₂ , C (O) H, C (O) OH, halogen, ^Re , SR ^e , S (O) ^Re , S (O) ₂ ^Re , S (O) OR ^e , S (O) ₂ OR ^e , OS (O) R ^e , OS (O) ₂ R ^e , OS (O) OR ^e , OS (O) ₂ OR ^e , OR ^e , NHR ^e , N (R ^e ) R ^f , ⁺ N (R ^e ) (R ^f ) R ^g , P (O) (OR ^e ) (OR ^f ), OP (O) (OR ^e ) (OR ^f ), SiR ^e R ^f R ^g , C (O) R ^e , C (O) OR ^e , C (O) N (R ^e ) R ^f , OC (O) R ^e , OC (O) OR ^e , OC (O) N (R ^e ) R ^f , N (R ^e ) C (O) R ^f , N (R ^e ) C (O) OR ^f , N (R ^e ) C (O) N (R ^f ) R ^g and a water-soluble group, where

R ^e , R ^f and R ^{g are} independently selected from H and optionally substituted (CH ₂ CH ₂ O) _ee CH ₂ CH ₂ X ¹³ R ^e1 , C _1-15 alkyl, C _1-15 heteroalkyl, C _3-15 cycloalkyl, C _1-15 heterocycloalkyl, C _5-15 aryl or C _1-15 heteroaryl, where ee is 1-1000, X ^{13 is} selected from O, S and NR ^f1 , and R ^f1 and R ^{e1 are} independently selected from H and C _{1- 3} alkyl, one or more of the optional substituents in R ^e , R ^f and / or R ^g are optionally a water-soluble group, two or more of R ^e , R ^f and R ^{g are} optionally joined by one or more bonds to form one or more optionally substituted carbocycles and / or g terotsiklov,

or R ⁵ + R ^{5 '} and / or R ⁶ + R ^6' and / or R ⁷ + R ^{7 'are} independently selected from = O, = S, = NOR ^e3 , = C (R ^e3 ) R ^e4 and = NR ^e3 , R ^e3 and R ^{e4 are} independently selected from H and optionally substituted C _1-3 alkyl, or R ^{5 ′} + R ^{6 ′} and / or R ^{6 ′} + R ^{7 ′} and / or R ^{7 ′} + R ^{14 ′ are} absent, which gives a double bond between atoms bearing R ^{5 '} and R ^6' , and / or R ^{6 '} and R ^7' , and / or R ^{7 '} and R ^14' , respectively, two or more of R ⁵ , R ^{5 '} , R ⁶ , R ^{6 '} , R ⁷ , R ^7' , R ¹⁴ and R ^{14 'are} optionally joined by one or more bonds to form one or more optionally substituted carbocycles and / or heterocycles;

X ^{1 is} selected from O, S and NR ¹³ , where R ^{13 is} selected from H and optionally substituted C _1-8 alkyl or C _1-8 heteroalkyl and is not connected to other substituents;

X ³ selected from O, S, C (R^fifteen) R^fifteen', -C (R^fifteen) (R^fifteen') -C (R^fifteen'') (R^fifteen''') -, -N (R^fifteen) -N (R^fifteen') -, -C (R^fifteen) (R^fifteen') -N (R^fifteen'') -, -N (R^fifteen'') -C (R^fifteen) (R^fifteen') -, -C (R^fifteen) (R^fifteen') -O-, -O-C (R^fifteen) (R^fifteen') -, -C (R^fifteen) (R^fifteen') -S-, -S-C (R^fifteen) (R^fifteen') -, -C (R^fifteen) = C (R^fifteen') -, = C (R^fifteen) -C (R^fifteen') =, -N = C (R^fifteen') -, = N-C (R^fifteen') =, -C (R^fifteen) = N-, = C (R^fifteen) -N =, -N = N-, = N-N =, CR^fifteen, N and NR^fifteen, or inDB1 andDB2 -X ³- represents -X ^3a andX ^3b- whereX ^3a associated withX ³⁴a double bond is present betweenX ³⁴ andX ^four , andX ^3b associated withX ^eleven, WhereX ^3a independently selected from H and optionally substituted (CH₂CH₂O)_eeCH₂CH₂ X ¹³R^e1, C_1-8alkyl or C_1-8 heteroalkyl and is not connected to other substituents;

X ^{4 is} selected from O, S, C (R ¹⁶ ) R ^{16 '} , NR ¹⁶ , N, and CR ¹⁶ ;

X ^{5 is} selected from O, S, C (R ¹⁷ ) R ^{17 ′} , NOR ¹⁷ and NR ¹⁷ , where R ¹⁷ and R ^{17 ′ are} independently selected from H and optionally substituted C _1-8 alkyl or C _1-8 heteroalkyl and not connected to other substituents;

X ^{6 is} selected from CR ¹¹ , CR ¹¹ (R ^{11 ′} ), N, NR ¹¹ , O, and S;

X ^{7 is} selected from CR ⁸ , CR ⁸ (R ^{8 '} ), N, NR ⁸ , O, and S;

X ^{8 is} selected from CR ⁹ , CR ⁹ (R ^{9 '} ), N, NR ⁹ , O, and S;

X ^{9 is} selected from CR ¹⁰ , CR ¹⁰ (R ^{10 ′} ), N, NR ¹⁰ , O, and S;

X ^{10 is} selected from CR ²⁰ , CR ²⁰ (R ^{20 '} ), N, NR ²⁰ , O, and S;

X ^{11 is} selected from C, CR ²¹ and N, or X ¹¹ —X ^{3b is} selected from CR ²¹ , CR ²¹ (R ^{21 ′} ), N, NR ²¹ , O, and S;

X ^{12 is} selected from C, CR ²² and N;

X ^{6 *},X ^{7 *},X ^8*,X ^9*,X ^10* andX ^eleven* have the same meanings as defined forX ⁶,X ⁷,X ⁸,X ⁹,X ¹⁰ andX ^eleven, respectively, and independently selected;

X ^{34 is} selected from C, CR ²³ and N;

the ring atom B in X ^{11 *} in DB6 and DB7 is connected to the ring atom of ring A in such a way that ring A and ring B in DB6 and DB7 are directly connected through a direct connection;

подразумевает, что указанная связь может быть прямой связью или некумулированной, необязательно делокализованной, двойной связью;

implies that said bond may be a direct bond or an uncumulated, optionally delocalized, double bond;

R ⁸ , R ^{8 '} , R ⁹ , R ^9' , R ¹⁰ , R ^{10 '} , R ¹¹ , R ^11' , R ¹⁵ , R ^{15 '} , R ^15'' , R ^15''' , R ¹⁶ , R ^{16 '} , R ²⁰ , R ^20' , R ²¹ , R ^{21 '} , R ²² and R ²³ , each independently selected from H, OH, SH, NH ₂ , N ₃ , NO ₂ , NO, CF ₃ , CN , C (O) NH ₂ , C (O) H, C (O) OH, halogen, R ^h , SR ^h , S (O) R ^h , S (O) ₂ R ^h , S (O) OR ^h , S (O) ₂ OR ^h , OS (O) R ^h , OS (O) ₂ R ^h , OS (O) OR ^h , OS (O) ₂ OR ^h , OR ^h , NHR ^h , N (R ^h ) R ⁱ , ⁺ N (R ^h ) (R ⁱ ) R ^j , P (O) (OR ^h ) (OR ⁱ ), OP (O) (OR ^h ) (OR ⁱ ), SiR ^h R ⁱ R ^j , C ( O) R ^h , C (O) OR ^h , C (O) N (R ^h ) R ⁱ , OC (O) R ^h , OC (O) OR ^h , OC (O) N (R ^h ) R ⁱ , N (R ^h ) C (O) R ⁱ , N (R ^h ) C (O) OR ⁱ , N (R ^h ) C (O) N (R ⁱ ) R ^j and a water-soluble group, where

R ^h , R ⁱ and R ^{j are} independently selected from H and optionally substituted (CH ₂ CH ₂ O) _ee CH ₂ CH ₂ X ¹³ R ^e1 , C _1-15 alkyl, C _1-15 heteroalkyl, C _3-15 cycloalkyl, C _1-15 heterocycloalkyl, C _5-15 aryl or C _1-15 heteroaryl, one or more of the optional substituents on R ^h , R ⁱ and / or R ^j are optionally a water soluble group, two or more of R ^h , R ⁱ and R ^j optionally connected by one or more bonds with the formation of one or more optionally substituted carbocycles and / or heterocycles,

or R ⁸ + R ^{8 '} and / or R ⁹ + R ^9' and / or R ¹⁰ + R ^{10 '} and / or R ¹¹ + R ^11' and / or R ¹⁵ + R ^{15 '} and / or R ^15'' + R ^{15 '''} and / or R ¹⁶ + R ^16' and / or R ²⁰ + R ^{20 '} and / or R ²¹ + R ^{21' are} independently selected from = O, = S, = NOR ^h1 , = C (R ^h1 ) R ^h2 and = NR ^h1 , R ^h1 and R ^{h2 are} independently selected from H and optionally substituted C _1-3 alkyl, two or more of R ⁸ , R ^{8 '} , R ⁹ , R ^9' , R ¹⁰ , R ^{10 '} , R ¹¹ , R ^11' , R ¹⁵ , R ^{15 '} , R ^15'' , R ^15''' , R ¹⁶ , R ^{16 '} , R ²⁰ , R ^20' , R ²¹ , R ^{21 '} , R ²² and R ²³ optionally connected by one or more bonds to form one or more optionally substituted carbocycles and / or heterocycles;

R ^8b and R ^{9b are} independently selected and have the same meanings as defined for R ⁸ , except that they cannot be connected to any other substituent;

one of R ⁴ and R ^{4 '} and one of R ¹⁶ and R ^16' may optionally be closed by one or more bonds to form one or more optionally substituted carbocycles and / or heterocycles;

one of R ² , R ^{2 '} , R ³ and R ^3' and one of R ⁵ and R ^{5 '} may optionally be closed by one or more bonds to form one or more optionally substituted carbocycles and / or heterocycles; and

a and b are independently selected from 0 and 1.

In an additional aspect, the present invention relates to a compound of formula ( I ′ ) or ( II ′ ):

,

,

or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein all substituents have the same meanings as defined for compounds of formula ( I ) and ( II ). Compounds of formula ( I ) and ( II ) are believed to be converted to compounds of formula ( I ' ) and ( II' ), respectively, in vivo with concomitant removal of HR ¹ , as schematically shown in FIG. 1 for a compound of formula ( I ).

Thus, the present invention relates to a compound of formula ( I ′ ) or ( II ′ ), said compound containing a cyclopropyl group that can be formed by rearrangement and concomitant removal of HR ¹ from a compound of formula ( I ) or ( II ). All embodiments for a compound of formula ( I ) or ( II ) or a group thereof also relate to a compound of formula ( I ' ) or ( II' ) or a group thereof, unless otherwise indicated in the context.

In a more specific embodiment, the present invention relates to a compound of formula ( I ) or ( II ), as described above herein, where

a) the DB fragment does not include the fragment DA1 , DA2 , DA1 ' or DA2' ; and

b) ring B in DB1 is a heterocycle; and

c) if X ³ in DB1 is - X ^3a and X ^3b - and ring B is aromatic, then two adjacent substituents on said ring B are combined to form an optionally substituted carbocycle or heterocycle fused to said ring B ; and

d) if X ³ in DB2 is - X ^3a and X ^3b - and ring B is aromatic, then two adjacent substituents on said ring B are combined to form an optionally substituted heterocycle fused to said ring B , an optionally substituted non-aromatic carbocycle fused to said ring B, or substituted aromatic carbocycle, which is fused with said ring B is connected and to which at least one substituent which contains a hydroxy group, a primary amino group or toricity amino group, a primary or secondary amine, a non-ring atom in the aromatic ring system which is not part of the amide; and

e) if ring A in DB2 is a 6-membered aromatic ring, then the substituents on ring B are not linked to form a ring fused to ring B ; and

f) two adjacent substituents on ring A in DB8 are combined to form an optionally substituted carbocycle or heterocycle fused to said ring A to form a bicyclic group with which other rings are not fused; and

g) ring A in DB9, together with any rings condensed with said ring A, contains at least two ring heteroatoms.

In another, more specific embodiment, the present invention relates to a compound of formula ( I ) or ( II ) as described herein above, wherein at least one of the substituents R ¹ , R ⁵ , R ^{5 '} , R ⁶ , R ^{6 '} , R ⁷ , R ^7' , R ¹⁴ , R ^{14 '} , R ⁸ , R ^8' , R ⁹ , R ^{9 '} , R ¹⁰ , R ^10' , R ¹¹ , R ^{11 '} , R ¹⁵ , R ^{15 '} , R ^15'' , R ^15'' , R ¹⁶ , R ^16' , R ²⁰ , R ^{20 '} , R ²¹ , R ^21' , R ²² and R ²³ contains the group X ¹⁴ (CH ₂ CH ₂ O ) _ff CH ₂ CH ₂ X ¹⁴ , where ff is 1-1000 and each of X ^{14 is} independently selected from

which is connected to the point of attachment of the indicated substituent either by a direct bond or by a group, being part of the same specified substituent, which does not include disulfide, hydrazone, hydrazide, ester, natural amino acid or peptide containing at least one natural an amino acid, and in which, if ring B in DB1 is a ring consisting only of carbon atoms, X ³ is O or NR ¹⁵ , X ⁴ is CH, X ³⁴ is C, there is only one group X ¹⁴ (CH ₂ CH ₂ O) _ff CH ₂ CH ₂ X ^14, Preece stvuyuschaya in said compound of formula (I) or (II), and said group is part of R ^6, R ^7, R ^8, R ¹⁰ or R ^15, then b = 1 and ff equal ≥5.

A compound of formula ( I ) or ( II ) or a conjugate thereof in which ff is greater than 1000 is included in the present invention.

In another more specific embodiment, the present invention relates to a compound of formula ( I ) or ( II ) as described herein above, wherein at least one of the substituents R ¹ , R ⁵ , R ^{5 '} , R ⁶ , R ^{6 '} , R ⁷ , R ^7' , R ¹⁴ , R ^{14 '} , R ⁸ , R ^8' , R ⁹ , R ^{9 '} , R ¹⁰ , R ^10' , R ¹¹ , R ^{11 '} , R ¹⁵ , R ^{15 '} , R ^15'' , R ^15''' , R ¹⁶ , R ^{16 '} , R ²⁰ , R ^20' , R ²¹ , R ^{21 '} , R ²² and R ²³ contains a triazole group.

It should be noted that this document, in its entirety, when referring to a compound of formula ( I ) or ( II ), includes references to a compound of formula ( I ' ) or ( II' ), respectively, if this does not apply to structural parts ( I ) and ( II ) not present in ( I ' ) and ( II' ), or in the context is not indicated otherwise. Similarly, when referring to a structural part (fragment), a linker-agent conjugate, or a conjugate obtained from a compound of formula ( I ) or ( II ), reference is made to a similar structural part (fragment), a linker-agent conjugate or conjugate obtained from a compound formulas ( I ' ) or ( II' ), respectively, unless this applies to structural parts ( I ) and ( II ) not present in ( I ' ) and ( II' ), or otherwise indicated in the context.

You must also take into account that when reference is made to a compound of formula ( I ) or ( II ) or a fragment, derivative or conjugate thereof, and a volume of R ^{2 ′} or R ^{12 is} defined, this description only refers to a compound of formula ( I ), since R ^{2 '} and R ^{12 are} absent in the compound of formula ( II ). Thus, throughout this document, where “R ^{2 '} ” or “R ¹² ” is present, “R ^2' (if present)” or “R ¹² (if present)” can be read, respectively. This also applies to (other) substituents that may or may not be present in the compounds of formulas ( I ) and ( II ) and fragments thereof, linker-agent conjugates and conjugates.

You must also take into account that the present invention relates to enantiomerically pure and / or diastereomerically pure compounds of the formulas ( I ) and ( II ), as well as to enantiomeric and / or diastereomeric mixtures of the compounds of the formulas ( I ) and ( II ).

An analysis of the substitution effects and effects of linkers, DNA alkylating units and DNA binding units in the compounds of formulas ( I ) and ( II ), their cyclopropyl-containing analogs and their conjugates and linker-agent conjugates described herein are presented without specific analysis a mechanism of action for compounds of formulas ( I ) and ( II ), their cyclopropyl-containing analogues, and their linker-agent conjugates and conjugates.

Compounds of formula ( I ) and ( II ) can be considered to create a DNA binding group ( DB ) and a DNA alkylating group ( DA1 , DA2 , DA1 ' or DA2' ), as shown in the figures above.

The DNA alkylating group of the compounds of formulas ( I ) and ( II ) is believed to contain an alkylation site. Alkylation of DNA can occur through the action of DNA on a carbon bearing R ¹ in a compound of formula ( I ) or ( II ), or on a similar carbon in a cyclopropyl-containing analog of said compound.

The DNA binding group of the compounds of formulas ( I ) and ( II ) is believed to contribute to the effective binding of these compounds to DNA. It can be linked to a DNA alkylating group via, for example, an amide bond. Thus, in one embodiment, X ⁵ is O.

In one embodiment, the present invention relates to a compound of formula ( I ). In another embodiment, the present invention relates to a compound of formula ( II ).

R ¹ in the compound of formula ( I ) or ( II ) represents a leaving group.

In one embodiment, the leaving group R ^{1 is} selected from halogen, azide (N ₃ ), carboxylate [OC (O) R ⁿ ], carbonate [OC (O) OR ⁿ ], carbamate [OC (O) N (R ⁿ ) R ⁿ¹ ] and OS (O) ₂ R ^o , where R ⁿ , R ⁿ¹ and R ^{o are} independently selected from H and optionally substituted C _1-10 alkyl, C _1-10 heteroalkyl, C _5-10 aryl, or C _1-10 heteroaryl. An optional substituent may be an oligoethylene glycol or polyethylene glycol group. When the group R ¹ contains an oligoethylene glycol or polyethylene glycol group, i.e. group X ¹⁴ (CH ₂ CH ₂ O) _ff CH ₂ CH ₂ X ¹⁴ , the compound of formula ( I ) or ( II ) or its conjugate may exhibit improved physicochemical, biopharmaceutical, pharmacodynamic and / or pharmacokinetic properties, which, as indicated herein above, may also be effective in the presence of oligoethylene glycol or polyethylene glycol groups at other positions in the compound of formula ( I ) or ( II ). In addition, however, the relatively large size of the substituent R ¹ may weaken the non-specific alkylation of the compound of formula ( I ) or ( II ) or its conjugate. In addition, the group R ¹ will be removed when the compound of formula ( I ) or ( II ) is rearranged into a compound of formula ( I ' ) or ( II' ). This means that the oligoethylene glycol or polyethylene glycol group may not have a negative effect on the cytotoxic potential of the compound of formula ( I ) or ( II ).

In one embodiment, the implementation of the group R ¹ selected from halogen and OS (O) ₂ R ^o . In another embodiment, the leaving group R ¹ in the compound of formula ( I ) or ( II ) is halogen. In another embodiment, the R ¹ group is selected from chlorine (Cl), bromine (Br), and iodine (I). In yet another embodiment, R ¹ represents chlorine (Cl). In yet another embodiment, R ¹ represents bromine (Br). In yet another embodiment, R ¹ is OS (O) ₂ R ^o . In yet another embodiment, R ¹ is OS (O) ₂ R ^o , and R ^o contains a group X ¹⁴ (CH ₂ CH ₂ O) _ff CH ₂ CH ₂ X ¹⁴ . In yet another embodiment, R ^{1 is} selected from OS (O) ₂ CF ₃ , OS (O) ₂ C ₆ H ₄ CH _3, and OS (O) ₂ CH ₃ .

By changing the leaving group R ¹ , it is possible to control the alkylating activity of the seco agents and to influence the rate of transformation of the seco agent into a cyclopropyl-containing agent of the formula ( I ′ ) or ( II ′ ). If the R ¹ removal ability is good enough, this can cause the seco agent to turn into a non-specific alkylating agent that can lower the cytotoxicity index and therapeutic index of the conjugates of the compounds of formulas ( I ) and ( II ), since the agent, for example, may be capable of alkylating, being bound in the conjugate. On the other hand, if R ¹ is a sufficiently poor removable group, the seco agent cannot complete the formation of the cyclopropyl-containing agent, which is believed to be an active type that can reduce its cytotoxicity and cytotoxicity index. Thus, in one embodiment, the Sven-Scott parameter s of the alkylating site is greater than 0.3. In other embodiments, the Sven-Scott parameter s is greater than 0.5 or 0.7 or 1.0.

The size of R ¹ may affect the rate of non-DNA alkylation of the compounds of formula ( I ) or ( II ) or its conjugate. If R ¹ is a relatively large group, nonspecific alkylation may be weakened, since carbon bearing R ¹ is somewhat protected.

Another way to control alkylating activityseco agents and their cyclopropyl-containing derivatives may be a partial protection of carbon to which the leaving group R^one attached to or in respect of which nucleophilic effects may occur by selecting at least one of R², R^{2 '}, R³, R^{3 '}, R^four, R^four', R⁵, R^5', R⁶, R^{6 '}, R¹², R¹⁶ and R^16'not representing hydrogen. Protection of said carbon may weaken nonspecific alkylation using compounds of formulas (I) and (II), their cyclopropyl-containing analogues and their conjugates. Although the presence of a steric hindrance may also affect the rate of DNA alkylation, it can reasonably be assumed that nonspecific alkylation may be relatively more affected than DNA alkylation, since the latter appears to occur after the agent is ideally positioned for nucleophilic exposure, bound to DNA by a small furrow. Carbon Bearing R^one in the compound of the formula (II), which is a secondary carbon atom (when R² represents H), is already partially protected compared to carbon bearing R^one in the compound of the formula (I) when R² and R^{2 '} both are H. In this regard, a compound of formula (II) can be compared with a compound of the formula (I) in which R^{2 '} is other than hydrogen. Additional protection may, however, be performed by selecting one or more of R², R³, R^{3 '}, R^four, R^four', R⁵, R^5', R⁶, R^{6 '}, R¹⁶ and R^16'not representing hydrogen.

In one embodiment, R ² and R ^{2 ′ are} both hydrogen. In another embodiment, R ^{2 ′} is hydrogen, and R ^{2 is} not hydrogen. In another embodiment, R ^{2 is} selected from N ₃ , NO ₂ , NO, CF ₃ , CN, C (O) NH ₂ , C (O) H, C (O) OH, halogen, R ^a , SR ^a , S ( O) R ^a , S (O) ₂ R ^a , S (O) OR ^a , S (O) ₂ OR ^a , OS (O) R ^a , OS (O) ₂ R ^a , OS (O) OR ^a , OS (O) ₂ OR ^a , OR ^a , N (R ^a ) R ^b , ⁺ N (R ^a ) (R ^b ) R ^c , P (O) (OR ^a ) (OR ^b ), OP (O) ( OR ^a ) (OR ^b ), SiR ^a R ^b R ^c , C (O) R ^a , C (O) OR ^a , C (O) N (R ^a ) R ^b , OC (O) R ^a , OC ( O) OR ^a , OC (O) N (R ^a ) R ^b , N (R ^a ) C (O) R ^b , N (R ^a ) C (O) OR ^b and N (R ^a ) C (O) N (R ^b ) R ^c where R ^a , R ^b and R ^{c are} independently selected from H and optionally substituted C _1-3 alkyl or C _1-3 heteroalkyl.

In one embodiment, R ^{2 is} selected from optionally substituted C _1-3 alkyl and C _1-3 heteroalkyl. In another embodiment, R ² is optionally substituted C _1-3 alkyl. In another embodiment, R ^{2 is} selected from methyl, ethyl, propyl and isopropyl. In another embodiment, R ² is methyl.

In yet another embodiment, R ² and R ^{2 'are} both not hydrogen. In one embodiment, both R ² and R ^{2 ′} are methyl.

Alternatively, or simultaneously, the steric protection of the carbon bearing R ¹ can be applied by selecting one or more of R ³ , R ^{3 '} , R ⁴ , R ^4' , R ¹² , R ¹⁶ and R ^{16 '} , which are not hydrogen . In one embodiment, the implementation of R ³ , R ^{3 '} , R ⁴ and R ^4' each represent H. In another embodiment, R ³ and R ^{3 '} both represent H. In another embodiment, R ⁴ and R ^4' both are H. In another embodiment, one of R ³ and R ^{3 ′} is C _1-3 alkyl, while the other is H. In another embodiment, one of R ⁴ and R ^{4 ′} is C _1-3 alkyl, then the other represents H. In another embodiment, one of R ³ and R ^{3 'represents} a C _1-3 alkyl, and one of R ⁴ and R ^4' represents from oh C _1-3 alkyl then the other represents H. In another embodiment, both R ³ and R ^{3 'are} independently C _1-3 alkyl. In another embodiment, both R ⁴ and R ^{4 ′} are independently C _1-3 alkyl. In another embodiment, one of R ³ , R ^{3 ′} , R ⁴ and R ^{4 ′} is methyl. In another embodiment, one of R ⁴ and R ^{4 ′} is methyl. In yet another embodiment, both R ⁴ and R ^{4 ′} are methyl. In another embodiment, one or both of R ⁴ and R ^{4 ′} is fluoro.

In one embodiment, R ¹² is H. In another embodiment, R ¹² is C _1-3 alkyl. In another embodiment, R ¹² is methyl or ethyl. In yet another embodiment, R ¹² is C (R ^{2 ′} ) (R ² ) R ¹ , which means that carbon carrying R ¹² carries two identical groups.

In another embodiment, R ¹⁶ and R ^{16 'are} both H. In another embodiment, R ¹⁶ is H. In other embodiments, R ¹⁶ is fluoro (F) or methyl or ethyl.

Alkylating activity of the compounds of formula (I) or (II) or its cyclopropyl-containing analogue may also be influenced by natureX ^one. NatureX ^one may affect the speed and conditions under whichseco the agents close the ring to cyclopropyl analogues, and / or to the speed at which the cyclopropyl ring opens by nucleophilic action (via DNA), and thus affects the nature of the alkylation. In one embodimentX ^one represents O. In another embodiment, the implementationX ^one represents NR¹³.

R substituents⁵, R^5', R⁶, R^{6 '}, R⁷, R^{7 '} andX ², as well as the size of the ring connected to the left side of the ring bearingX ^one, can, for example, each, independently, or two or more taken together, affect the pharmacological properties of the agent, for example, affect water solubility, affect the parameters of aggregation, affect the process of DNA alkylation and / or affect DNA -binding ability. In addition, in particular, R⁵ and R^5', as well as to some extent R⁶ and R^{6 '}, may also affect the degree of carbon protection for which nucleophilic exposure is to occur.

R ⁵ and R ^{5 ′} may both be H, or R ⁵ may be H, while R ^{5 ′ is} absent. In another embodiment, at least one of R ⁵ and R ^{5 ′ is} not hydrogen and is not absent. In another embodiment, R ^{5 is} not hydrogen.

In one embodiment, R ^{5 is} selected from OH, SH, NH ₂ , N ₃ , NO ₂ , NO, CF ₃ , CN, C (O) NH ₂ , C (O) H, C (O) OH, halogen, R ^e2 , SR ^e2 , S (O) R ^e2 , S (O) ₂ R ^e2 , S (O) OR ^e2 , S (O) ₂ OR ^e2 , OS (O) R ^e2 , OS (O) ₂ R ^e2 , OS (O) OR ^e2 , OS (O) ₂ OR ^e2 , OR ^e2 , NHR ^e2 , N (R ^e2 ) R ^f2 , ⁺ N (R ^e2 ) (R ^f2 ) R ^g2 , P (O) (OR ^e2 ) (OR ^f2 ), OP (O) (OR ^e2 ) (OR ^f2 ), SiR ^e2 R ^f2 R ^g2 , C (O) R ^e2 , C (O) OR ^e2 , C (O) N (R ^e2 ) R ^f2 , OC (O) R ^e2 , OC (O) OR ^e2 , OC (O) N (R ^e2 ) R ^f2 , N (R ^e2 ) C (O) R ^f2 , N (R ^e2 ) C (O) OR ^f2 and N (R ^e2 ) C (O) N (R ^f2 ) R ^g2 , where R ^e2 , R ^f2 and R ^{g2 are} independently selected from H and optionally substituted C _1-3 alkyl, C _1-3 heteroalkyl, C ₃ cycloalkyl or C _1-3 heterocycloalkyl, two or more of R ^e2, R ^f2 and R ^g2 are optionally joined by one or more bonds to form one or more optionally substituted carbocycles and / or heterocycles.

In another embodiment, R ^{5 is} selected from nitro, halogen, amino, cyano, hydroxy and optionally substituted C _1-3 alkylamino, di (C _1-3 alkyl) amino, C _1-3 alkylcarbonylamino, C _1-3 alkoxycarbonylamino, C _{1 -3} alkylaminocarbonylamino, C _1-3 alkyloxy, C _1-3 alkylcarbonyloxy, C _1-3 alkoxycarbonyloxy, C _1-3 alkylaminocarbonyloxy or C _1-3 alkyl. In yet another embodiment, R ⁵ is an optionally substituted linear C _1-3 alkyl. In another embodiment, R ⁵ is an unsubstituted linear C _1-3 alkyl. In another embodiment, R ^{5 is} selected from methyl, ethyl, propyl, isopropyl, nitro, CF ₃ , F, Cl, Br, cyano, methoxy, ethoxy, propoxy, isopropoxy, amino (NH ₂ ), methylamino, formyl, hydroxymethyl and dimethylamino . In another embodiment, R ⁵ is methyl, ethyl, methoxy or ethoxy. In another embodiment, R ⁵ is methyl. In other embodiments, R ⁵ is ethyl or methoxy or ethoxy.

R ⁶ and R ^{6 ′} may both be hydrogen, or R ⁶ may be hydrogen, while R ^{6 ′ is} absent. In another embodiment, at least one of R ⁶ and R ^{6 ′ is} not hydrogen and is not absent. In another embodiment, R ^{6 is} not hydrogen.

R ⁵ and R ⁶ may be coupled to form, together with the two carbon atoms to which they are attached, an optionally substituted 5- or 6-membered ring. This ring, for example, may be a dihydropyrrole, dihydrofuran, cyclopentene, 1,3-dioxolene, pyrrolidine, tetrahydrofuran, cyclopentane or a 1,3-dioxolane group.

The substituents R ¹⁶ and R ^{16 '} may affect the degree of carbon protection, for which nucleophilic effects also occur. In one embodiment, X ⁴ is CR ¹⁶ . In a further embodiment, R ¹⁶ is hydrogen. In yet another embodiment, R ¹⁶ is C _1-3 alkyl or C _1-3 heteroalkyl. In another embodiment, R ¹⁶ is methyl or ethyl. In yet another embodiment, R ¹⁶ is methyl. In yet another embodiment, R ¹⁶ is fluoro.

In one embodiment, the implementation of R ² , R ^{2 '} , R ³ , R ^3' , R ⁴ , R ^{4 '} , R ⁵ , R ^5' , R ⁶ , R ^{6 '} , R ¹² , R ¹⁶ and R ^16' represent each hydrogen. In another embodiment, R ² , R ^{2 '} , R ³ , R ^3' , R ⁴ , R ^{4 '} , R ^5' , R ⁶ , R ^{6 '} , R ¹² , R ^16, and R ^16' are each hydrogen. In yet another embodiment, R ² , R ^{2 '} , R ³ , R ^3' , R ⁴ , R ^{4 '} , R ⁵ , R ^5' , R ⁶ , R ^{6 '} , R ⁷ , R ^7' , R ¹² , R ¹⁴ , R ^{14 '} , R ¹⁶ , R ^16' and R ¹⁹ each represent hydrogen. In yet another embodiment, R ² , R ^{2 '} , R ³ , R ^3' , R ⁴ , R ^{4 '} , R ^5' , R ⁶ , R ^{6 '} , R ⁷ , R ^7' , R ¹² , R ¹⁴ , R ^{14 '} , R ¹⁶ , R ^16' and R ¹⁹ each represent hydrogen.

Although the rate of alkylation and the effectiveness of compounds of the formula (I) and (II) can optionally be regulated in several ways, in one aspect of the present invention this can be achieved by the introduction of steric protection, choosing for the compound of the formula (I) one or more of R², R^{2 '}, R³, R^{3 '}, R^four, R^four', R⁵, R^5', R⁶, R^{6 '}, R¹², R¹⁶ and R^16'not representing hydrogen, and for the compounds of formula (II) one or more of R², R³, R^{3 '}, R^four, R^four', R⁵, R^5', R⁶, R^{6 '}, R¹⁶ and R^16'not representing hydrogen. Substituents should not cause too much steric hindrance, however, especially when more than one of these substituents is other than hydrogen, as this could have a negative effect on DNA alkylation. In addition, this may provide less efficient binding in the DNA of the minor furrow and may cause synthesis difficulties.

In one aspect of the present invention, at least one of R ¹ , R ⁵ , R ^{5 '} , R ⁶ , R ^6' , R ⁷ , R ^{7 '} , R ¹⁴ , R ^14' , R ⁸ , R ^{8 '} , R ⁹ , R ^{9 '} , R ¹⁰ , R ^10' , R ¹¹ , R ^{11 '} , R ¹⁵ , R ^15' , R ^{15 ''} , R ^{15 '''} , R ¹⁶ , R ^16' , R ²⁰ , R ^{20 '} , R ²¹ , R ^21' , R ²² and R ²³ contains a group X ¹⁴ (CH ₂ CH ₂ O) _ff CH ₂ CH ₂ X ¹⁴ , where ff is 1-1000 and each of X ^{14 is} independently selected from

This group must be linked to the core of the DNA alkylating group or DNA binding group via a direct bond or via a crosslinking link which is part of the same R group and which does not include disulfide, hydrazone, hydrazide, ester, natural amino acid or peptide containing at least one natural amino acid. Said crosslinking unit should preferably be cleaved by less than 20%, more preferably less than 10%, and most preferably less than 5% within 24 hours when the compound of formula ( I ) or ( II ) is administered in vivo.

The group X ¹⁴ (CH ₂ CH ₂ O) _ff CH ₂ CH ₂ X ¹⁴ , for example, can be selected from

where ff 'is selected from values from 1 to 1000. In more specific embodiments, ff' is selected from values from 1 to 100 or from 1 to 10. In other embodiments, ff 'is 1 or 2 or 3 or 4. In another embodiment ff 'is 3 or 4.

The oligoethylene glycol or polyethylene glycol group or its derivative is connected via a crosslinking link to the core structure of the compound of formula ( I ) or ( II ). Such a crosslinking unit may be a single bond, wherein oligoethylene glycol or polyethylene glycol or a derivative thereof are bonded to the core structure via, for example, an amine, ether or sulfide bond. Alternatively, the oligoethylene glycol or polyethylene glycol group or its derivative may be linked to the structure of the nucleus via, for example, a carbamate, carbonate, amide, alkyl, heteroalkyl, aryl or heteroaryl group, or any combination thereof. In one embodiment, at least one of R ¹ , R ⁵ , R ^{5 ′} , R ⁶ , R ^{6 ′} , R ⁷ , R ^{7 ′} , R ¹⁴ , R ^{14 ′} , R ⁸ , R ^{8 ′} , R ⁹ , R ^{9 '} , R ¹⁰ , R ^10' , R ¹¹ , R ^{11 '} , R ¹⁵ , R ^15' , R ^{15 ''} , R ^{15 '''} , R ¹⁶ , R ^16' , R ²⁰ , R ^{20 '} , R ²¹ , R ^21' , R ²² and R ²³ selected from

where hh is 1-1000, X ^{15 is} selected from S and NR ³² , each of X ^{16 is} independently selected from O, S and NR ³⁴ , R ^{30 is} independently selected from H and optionally substituted C _1-10 alkyl, C _1-10 heteroalkyl , C _3-10 cycloalkyl, C _1-10 heterocycloalkyl, C _5-10 aryl or C _1-10 heteroaryl, R ³² , R ³³ and R ^{34 are} independently selected from H and C _1-3 alkyl, and R ³¹ has the same value as defined for R ⁷ . R ³⁰ , for example, may be selected from H, methyl, ethyl, methoxymethyl, p- aminobenzoyl and p-aminoanilinocarbonyl.

In a further embodiment, at least one of R ¹ , R ⁵ , R ^{5 '} , R ⁶ , R ^6' , R ⁷ , R ^{7 '} , R ¹⁴ , R ^14' , R ⁸ , R ^{8 '} , R ⁹ , R ^{9 '} , R ¹⁰ , R ^10' , R ¹¹ , R ^{11 '} , R ¹⁵ , R ^15' , R ^{15 ''} , R ^{15 '''} , R ¹⁶ , R ^16' , R ²⁰ , R ^{20 '} , R ²¹ , R ^21' , R ²² and R ²³ selected from

In another embodiment, R ^{1 is} selected from

In one embodiment, at least one of R ¹ , R ⁵ , R ^{5 ′} , R ⁶ , R ^{6 ′} , R ⁷ , R ^{7 ′} , R ¹⁴ , R ^{14 ′} , R ⁸ , R ^{8 ′} , R ⁹ , R ^{9 '} , R ¹⁰ , R ^10' , R ¹¹ , R ^{11 '} , R ¹⁵ , R ^15' , R ^{15 ''} , R ^{15 '''} , R ¹⁶ , R ^16' , R ²⁰ , R ^{20 '} , R ²¹ , R ^21' , R ²² and R ²³ contains the group X ¹⁴ (CH ₂ CH ₂ O) _ff CH ₂ CH ₂ X ¹⁴ . In another embodiment, at least one of R ⁵ , R ⁶ , R ⁷ and R ¹⁴ contains a group X ¹⁴ (CH ₂ CH ₂ O) _ff CH ₂ CH ₂ X ¹⁴ . In yet another embodiment, at least one of R ⁶ and R ⁷ contains a group X ¹⁴ (CH ₂ CH ₂ O) _ff CH ₂ CH ₂ X ¹⁴ . In yet another embodiment, at least one of R ⁸ , R ^{8 ′} , R ⁹ , R ^{9 ′} , R ¹⁰ , R ^{10 ′} , R ¹¹ , R ^{11 ′} , R ¹⁵ , R ^{15 ′} , R ^{15 ′ '} , R ^15''' , R ¹⁶ , R ^{16 '} , R ²⁰ , R ^20' , R ²¹ , R ^{21 '} , R ²² and R ²³ contains the group X ¹⁴ (CH ₂ CH ₂ O) _ff CH ₂ CH ₂ X ¹⁴ . In yet another embodiment, at least one of R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ²⁰ , R ²¹ and R ²² contains a group X ¹⁴ (CH ₂ CH ₂ O) _ff CH ₂ CH ₂ X ¹⁴ . In yet another embodiment, at least one of R ⁸ and R ⁹ contains a group X ¹⁴ (CH ₂ CH ₂ O) _ff CH ₂ CH ₂ X ¹⁴ . In yet another embodiment, at least R ¹ contains a group X ¹⁴ (CH ₂ CH ₂ O) _ff CH ₂ CH ₂ X ¹⁴ .

The compound of formula ( I ) or ( II ) may also contain 2 or more groups X ¹⁴ (CH ₂ CH ₂ O) _ff CH ₂ CH ₂ X ¹⁴ . In one embodiment, the compound of formula ( I ) or ( II ) contains 2 groups X ¹⁴ (CH ₂ CH ₂ O) _ff CH ₂ CH ₂ X ¹⁴ . In another embodiment, the compound of formula ( I ) or ( II ) contains 2 groups X ¹⁴ (CH ₂ CH ₂ O) _ff CH ₂ CH ₂ X ¹⁴ that are part of 2 separate groups R. It may be advantageous to place two or more groups X ¹⁴ (CH ₂ CH ₂ O) _ff CH ₂ CH ₂ X ¹⁴ at distant positions in the compound of formula ( I ) or ( II ), as this can protect the relatively hydrophobic core more efficiently.

The compounds of formula ( I ) and ( II ) may contain one or more oligoethylene glycol or polyethylene glycol groups or their derivatives. Such a group can improve the water solubility and aggregation parameters of the compounds of formula ( I ) or ( II ) and can cause increased activity against many drug resistant targets. If a compound of formula ( I ) or ( II ) with such a group is included in the conjugate, it is possible that an oligoethylene glycol or polyethylene glycol group is located between the progroup and the remainder of the compound of formula ( I ) or ( II ), or that is located in a position slightly opposite to at the point of attachment of the progroup, thus placing a residue of the compound of formula ( I ) or ( II ) between the progroup and the oligoethylene glycol or polyethylene glycol group. The latter condition may have an advantage in the sense of the water solubility of the conjugates. The improved water solubility of the compounds of formula ( I ) and ( II ) and their conjugates can lead to increased production and purity of the conjugates during the synthesis, for example, due to a decrease in the aggregate formation. In addition, the downward trend in aggregation and the high purity of the conjugate may, for example, lead to a decrease in the number of side effects after administration of the conjugate. In addition, the presence of one or more oligoethylene glycol and / or polyethylene glycol groups in the conjugate can reduce the secretion of the conjugate from the kidneys or liver, which increases the circulation rate in the body.

In another aspect of the present invention, the compounds of formula ( I ) and ( II ) may contain one or more triazole rings. The introduction of a 1,2,3-triazole ring may provide an advantage in the synthesis, since two groups that ultimately can join the 1,2,3-triazole ring can be attached to each other via said triazole ring using a mild and effective reaction cycloaddition between the alkyno and azide group. Due to the fact that the conditions for this cycloaddition reaction are very mild and correspond to almost all functional groups, the interaction can be performed at one of the last stages of the synthesis of a compound of formula ( I ) or ( II ), its linker-agent conjugate or conjugate, thereby providing easy preparation of a number of compounds of the formulas ( I ) and ( II ) and their conjugates for SAR (activity dependence on structure) studies.

Preferably, the triazole group is thus located in the DNA alkylating group or the DNA binding group, which can facilitate the binding of the compound to DNA. Additional DNA binding groups, such as indole or benzofuran groups, which are linked to a DNA binding or DNA alkylating group, can increase the effectiveness of the compound, presumably by enhancing DNA binding. These additional aromatic groups may, however, have an adverse effect on pharmacological properties such as water solubility. Triazole, which is an aromatic group, can also enhance DNA binding and thus increase the cytotoxic effectiveness of the compound, but since it is more polar than other aromatic fragments, such as the phenyl ring, negative effects on pharmacological properties may be less pronounced.

In one embodiment, the present invention relates to a compound of formula ( I ) or ( II ), wherein at least one of R ¹ , R ⁵ , R ^{5 ′} , R ⁶ , R ^{6 ′} , R ⁷ , R ^{7 ′} , R ¹⁴ , R ^{14 '} , R ⁸ , R ^8' , R ⁹ , R ^{9 '} , R ¹⁰ , R ^10' , R ¹¹ , R ^{11 '} , R ¹⁵ , R ^15' , R ^{15 ''} , R ^{15 '''} , R ¹⁶ , R ^16' , R ²⁰ , R ^{20 '} , R ²¹ , R ^21' , R ²² and R ²³ contains a triazole group.

In another embodiment, at least one of R ⁸ , R ^{8 '} , R ⁹ , R ^9' , R ¹⁰ , R ^{10 '} , R ¹¹ , R ^11' , R ¹⁵ , R ^{15 '} , R ^15'' , R ^{15 ″} , R ¹⁶ , R ^{16 ′} , R ²⁰ , R ^{20 ′} , R ²¹ , R ^{21 ′} , R ²² and R ²³ contains a triazole group. In another embodiment, at least one of R ⁸ , R ⁹ and R ¹⁰ contains a triazole group. In another embodiment, at least one of R ⁸ and R ⁹ contains a triazole group. In yet another embodiment, at least R ⁸ contains a triazole group.

In another embodiment, at least one of R ⁵ , R ^{5 ′} , R ⁶ , R ^{6 ′} , R ⁷ , R ^{7 ′} , R ¹⁴ and R ^{14 ′} contains a triazole group. In another embodiment, at least one of R ⁶ , R ^{6 '} , R ⁷ and R ^7' contains a triazole group. In yet another embodiment, R ¹ contains a triazole group.

For an optimal DNA binding effect, the triazole group can be linked via a linker that contains the triazole group in conjugation with or in the immediate vicinity of the nucleus of the DNA binding or DNA alkylating group. The linker, for example, may be a single bond, -N (R ³⁵ ) C (O) -, -C (O) N (R ³⁵ ) -, -C (O) -, -C (R ³⁵ ) (R ³⁶ ) -, -C (R ³⁵ ) = C (R ³⁶ ) -, -O-, -S- or -N (R ³⁵ ) -, where R ³⁵ and R ³⁶ are selected from H and optionally substituted C _1-4 alkyl or C _1-4 heteroalkyl, or to be any other optionally substituted small linker that does not have more than 4 linking atoms (for example, the group -N (R ²⁰ ) C (O) - has two linking atoms: N and C) between DNA- a linking unit or a DNA alkylating unit and a triazole ring.

The triazole ring may be 1,2,3-triazole or 1,2,4-triazole. In one embodiment, the triazole ring is 1,2,3-triazole. In another embodiment, the triazole is 1,2,4-triazole. The 1,2,3-triazole ring may be 4,5-, 1,5- or 1,4-disubstituted. If the 1,2,3-triazole ring is 1,4-substituted, this means that the substituent contained in the 1,2,3-triazole ring has an expanded shape. If the 1,2,3-triazole ring is 4,5- or 1,5-substituted, the 1,2,3-triazole ring actually forms a rotation and holds two substituents on the triazole in close proximity to each other. The triazole ring may also be located at the end of the substituent, with the triazole ring being only monosubstituted. Substitution in this case may be at N-1 or C-4. 1,2,4-Triazole may be 1,3-, 1,5- or 3,5-disubstituted. The substituent which contains 1,3- or 3,5-disubstituted 1,2,4-triazole has an expanded form, while in the 1,5-disubstituted 1,2,4-triazole, both substituents on triazole are in close proximity to each other from friend. The triazole ring may also be trisubstituted.

In one aspect, at least one of R ¹ , R ⁵ , R ^{5 '} , R ⁶ , R ^6' , R ⁷ , R ^{7 '} , R ¹⁴ , R ^14' , R ⁸ , R ^{8 '} , R ⁹ , R ^{9 '} , R ¹⁰ , R ^10' , R ¹¹ , R ^{11 '} , R ¹⁵ , R ^15' , R ^{15 ''} , R ^{15 '''} , R ¹⁶ , R ^16' , R ²⁰ , R ^{20 '} , R ²¹ , R ^21' , R ²² and R ²³ in the compound of formula ( I ) or ( II ) is

,

,

WhereX ^eighteen andX ¹⁹ selected from O, S, NR²⁵, H₂ and C (R²⁵) R²⁶where R²⁵ and R²⁶ selected from H and optionally substituted C_1-3 alkyl or C_1-3 heteroalkyl and R²⁴ has the same meaning as defined for R⁸, and is independently selected.

R ²⁴ , for example, may be selected from H and

where jj, jj 'and jj''are independently selected from values from 0 to 8, each tt, tt' and tt '' are independently selected from values 0 and 1, each of X ²¹ and X ^{22 is} independently selected from O, S, NR ⁶⁷ , H ₂ and C (R ⁶⁷ ) R ⁶⁸ , where R ⁶⁷ and R ^{68 are} independently selected from H and optionally substituted C _1-3 alkyl or C _1-3 heteroalkyl, and R ⁶⁶ selected from H, COOH, CO ₂ Me , OH, OMe, NR ⁶⁹ R ⁷⁰ , NR ⁶⁹ C (O) CH ₃ , SH, SMe,

,

,

WhereX ²³ selected from halogen, hydroxy, OC (O) R^bb and OC (O) OR^bb, or C (O) -X ²³ is an activated ester,X ²⁴ selected from halide, mesyloxy, triflyloxy and tosyloxy, R^bb selected from optionally substituted C_1-10 alkyl, C_1-10 heteroalkyl, C_3-10 cycloalkyl, C_1-10 heterocycloalkyl, C_5-10 aryl and c_1-10 heteroaryl and R⁶⁹, R⁷⁰ and R⁷¹ independently selected from methyl and H.

In other embodiments, at least one of R ⁵ , R ⁶ , R ^7, and R ¹⁴ , or at least one of R ⁸ , R ⁹ , R ^10, and R ¹¹ , or at least one of R ⁶ and R ⁷ , or at least one of R ⁸ and R ⁹ , or at least R ⁸ , or at least R ⁶ , or at least R ⁷ in the compound of the formula ( I ) or ( II ) represents

,

,

where R ²⁴ , X ¹⁸ and X ¹⁹ are as defined hereinabove.

In some embodiments, at least one of R ¹ , R ⁵ , R ^{5 ′} , R ⁶ , R ^{6 ′} , R ⁷ , R ^{7 ′} , R ¹⁴ , R ^{14 ′} , R ⁸ , R ^{8 ′} , R ⁹ , R ^{9 '} , R ¹⁰ , R ^10' , R ¹¹ , R ^{11 '} , R ¹⁵ , R ^15' , R ^{15 ''} , R ^{15 '''} , R ¹⁶ , R ^16' , R ²⁰ , R ^{20 '} , R ²¹ , R ^21' , R ²² and R ²³ , or at least one of R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ , or at least one of R ⁸ and R ⁹ , or at least R ⁸ , or at least one of R ⁵ , R ⁶ , R ⁷ and R ¹⁴ , or at least one of R ⁶ and R ⁷ in the compound of formula ( I ) or ( II ) is selected from

,

,

where R ³⁷ , R ³⁸ , R ³⁹ and R ^{40 are} independently selected from H and methyl.

In other embodiments, at least one of R ¹ , R ⁵ , R ^{5 '} , R ⁶ , R ^6' , R ⁷ , R ^{7 '} , R ¹⁴ , R ^14' , R ⁸ , R ^{8 '} , R ⁹ , R ^{9 '} , R ¹⁰ , R ^10' , R ¹¹ , R ^{11 '} , R ¹⁵ , R ^15' , R ^{15 ''} , R ^{15 '''} , R ¹⁶ , R ^16' , R ²⁰ , R ^{20 '} , R ²¹ , R ^21' , R ²² and R ²³ , or at least one of R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ , or at least one of R ⁸ and R ⁹ , or at least R ⁸ , or at least one of R ⁵ , R ⁶ , R ⁷ and R ¹⁴ , or at least one of R ⁶ and R ⁷ in the compound of formula ( I ) or ( II ) is selected from

where R ³⁸ , R ³⁹ and R ^{40 are} independently selected from H and methyl.

In other embodiments, at least one of R ¹ , R ⁵ , R ^{5 '} , R ⁶ , R ^6' , R ⁷ , R ^{7 '} , R ¹⁴ , R ^14' , R ⁸ , R ^{8 '} , R ⁹ , R ^{9 '} , R ¹⁰ , R ^10' , R ¹¹ , R ^{11 '} , R ¹⁵ , R ^15' , R ^{15 ''} , R ^{15 '''} , R ¹⁶ , R ^16' , R ²⁰ , R ^{20 '} , R ²¹ , R ^21' , R ²² and R ²³ , or at least one of R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ , or at least one of R ⁸ and R ⁹ , or at least R ⁸ , or at least one of R ⁵ , R ⁶ , R ⁷ and R ¹⁴ , or at least one of R ⁶ and R ⁷ in the compound of formula ( I ) or ( II ) is selected from

,

,

where R ³⁸ , R ³⁹ and R ^{40 are} independently selected from H and methyl.

In other embodiments, at least one of R ¹ , R ⁵ , R ^{5 '} , R ⁶ , R ^6' , R ⁷ , R ^{7 '} , R ¹⁴ , R ^14' , R ⁸ , R ^{8 '} , R ⁹ , R ^{9 '} , R ¹⁰ , R ^10' , R ¹¹ , R ^{11 '} , R ¹⁵ , R ^15' , R ^{15 ''} , R ^{15 '''} , R ¹⁶ , R ^16' , R ²⁰ , R ^{20 '} , R ²¹ , R ^21' , R ²² and R ²³ , or at least one of R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ , or at least one of R ⁸ and R ⁹ , or at least R ⁸ , or at least one of R ⁵ , R ⁶ , R ⁷ and R ¹⁴ , or at least one of R ⁶ and R ⁷ in the compound of formula ( I ) or ( II ) is selected from

,

,

where R ³⁸ , R ³⁹ and R ^{40 are} independently selected from H and methyl.

In one aspect, the compounds of formulas ( I ) and ( II ) are represented by compounds of formulas ( Ib ) and ( IIb ), respectively:

.

.

In one embodiment, X ² in ( Ib ) or ( IIb ) is N.

In a preferred embodiment, X ² in ( Ib ) or ( IIb ) is CR ¹⁴ .

In a further embodiment, X ² in ( Ib ) is CR ¹⁴ and a is 0.

In another embodiment, X ² in ( Ib ) or ( IIb ) is CH.

In yet another embodiment, R ⁵ in ( Ib ) or ( IIb ) is selected from nitro, halogen, amino, cyano, hydroxy and optionally substituted C _1-3 alkylamino, di (C _1-3 alkyl) amino, C _1-3 alkylcarbonylamino C _1-3 alkoxycarbonylamino C _1-3 alkylaminocarbonylamino C _1-3 alkyloxy C _1-3 alkylcarbonyloxy C _1-3 alkylaminocarbonyloxy or C _1-3 alkyl. In yet another embodiment, R ⁵ in ( Ib ) or ( IIb ) is an optionally substituted linear C _1-3 alkyl. In another embodiment, R ⁵ in ( Ib ) or ( IIb ) is an unsubstituted linear C _1-3 alkyl. In another embodiment, R ⁵ in ( Ib ) or ( IIb ) is methyl. In other embodiments, R ⁵ in ( Ib ) or ( IIb ) is ethyl or methoxy or ethoxy.

In yet another aspect, compounds of formulas ( I ) and ( II ) are represented by compounds of formulas ( Ic ) and ( IIc ), respectively:

.

.

In one embodiment, X ² in ( Ic ) or ( IIc ) is NH.

In yet another aspect, compounds of formulas ( I ) and ( II ) are represented by compounds of formulas ( Id ) and ( IId ), respectively:

.

.

In one embodiment, X ² in ( Id ) or ( IId ) is NH.

In another embodiment, the compounds of formulas ( I ) and ( II ) are represented by ( Ia ) and ( IIa ), respectively:

,

,

where DA1 is

or an isomer, or a mixture of its isomers.

In other embodiments, the compounds of formulas ( I ) and ( II ) are represented by ( Ia ) and ( IIa ), respectively:

,

,

where DA1 is

or an isomer of one of these compounds, or a mixture of isomers.

In other embodiments, the compounds of formulas ( I ) and ( II ) are represented by ( Ia ) and ( IIa ), respectively:

,

,

where DA1 is

or an isomer of one of these compounds, or a mixture of isomers.

In other embodiments, the compounds of formulas ( I ) and ( II ) are represented by ( Ia ) and ( IIa ), respectively:

,

,

where DA1 is

,

,

where r⁵⁴ selected from H and optionally substituted C_1-3 alkyl (e.g. methyl or trifluoromethyl), R⁵⁵ selected from H, methyl, ethyl and methoxy,X ²⁵ andX ²⁶ independently selected from O, S, CH₂ and NR⁵¹, and R⁵¹, R⁵² and R⁵³ independently selected from H, C_1-3 alkyl and

,

,

where ii, ii 'and ii''are independently selected from values from 0 to 8, each ss, ss' and ss '' are independently selected from values 0 and 1, each of X ²⁵ and X ^{26 is} independently selected from O, S, NR ⁵⁶ , H ₂ and C (R ⁵⁶ ) R ⁵⁷ , where R ⁵⁶ and R ^{57 are} independently selected from H and optionally substituted C _1-3 alkyl or C _1-3 heteroalkyl, and R ⁵⁸ selected from H, COOH, CO ₂ Me , OH, OMe, NR ⁵⁹ R ⁶⁰ , NR ⁵⁹ C (O) CH ₃ , SH, SMe,

WhereX ²⁷ selected from halogen, hydroxy, OC (O) R^aa and OC (O) OR^aa, or C (O) -X ²³ is an activated ester,X ²⁴ selected from halide, mesyloxy, triflyloxy and tosyloxy, R^aa selected from optionally substituted C_1-10 alkyl, C_1-10 heteroalkyl, C_3-10 cycloalkyl, C_1-10 heterocycloalkyl, C_5-10 aryl and c_1-10 heteroaryl and R⁵⁹, R⁶⁰ and R⁶¹ independently selected from methyl and H, or an isomer of one of these compounds, or a mixture of isomers.

In another embodiment, the compound of formula ( I ) or ( II ) is

or its isomer, or a mixture of isomers.

In another embodiment, the compound of formula ( I ) or ( II ) is

or its isomer, or a mixture of isomers.

In other embodiments, a compound of formula ( I ) or ( II ) is

or an isomer of one of these compounds, or a mixture of isomers.

In one embodiment, in the compound of formula ( I ) or ( II ), b = 1. In another embodiment, b = 0. In another embodiment, a = 0. In yet another embodiment, a = 0 and b = 1.

The increased water solubility of the compounds of formula ( I ) or ( II ) can be achieved not only by introducing water-soluble or polar groups such as a triazole group or an oligoethylene glycol or polyethylene glycol group or a combination thereof, but can also be achieved by replacing carbon ring atoms with heteroatoms, for example in the DNA binding group. Improved water solubility of the compounds of formulas ( I ) and ( II ) and their conjugates can lead to increased production and purity of the conjugates during the synthesis, for example, due to a decrease in the aggregate formation. In addition, the downward trend in aggregation and the high purity of the conjugate may, for example, lead to a decrease in the number of side effects after administration of the conjugate.

Increased metabolic degradation, for example, in the liver, can be achieved, for example, by introducing groups into DNA-binding groups, which can be relatively easily oxidized, for example, acetylene and alkene groups. Oxidation of toxic compounds is one of the mechanisms by which a mammal can detoxify such compounds. If the compounds of the present invention are absorbed in the liver, effective detoxification can, for example, overcome liver toxicity as a side effect.

The expansion of the π-conjugated system in the DNA-binding group can increase the binding affinity of the DNA-binding agent to DNA. The π-system can be expanded by the introduction of additional aromatic rings and / or conjugated double and / or triple bonds.

Progroups can be linked to DNA binding groups if a suitable functional group is present. This, for example, may be a hydroxyl group or a primary or secondary amino group. The binding of a progroup to a DNA binding unit in addition to or instead of an alkylating group, for example, X ¹ , may be advantageous. For example, the presence of two progroups can increase selective delivery to the target and / or activation and / or decrease in the amount of free substance in non-target regions, thereby reducing side effects and increasing the therapeutic index.

DNA binding group in compoundDbformulas (I) or (II) selected from structuresDB1-DB9:

.

.

In one embodiment, the DNA linking group contains at least two aromatic rings, of which at least one contains at least one ring atom, which is a heteroatom, or the DNA linking group contains at least at least a bicyclic aromatic system in which at least one ring atom is a heteroatom. In another embodiment, the DNA-binding group contains at least two aromatic rings, and both contain at least one ring atom, which is a heteroatom, or the DNA-binding group contains at least a bicyclic aromatic system, in which at least two ring atoms are a heteroat.

In one aspect of the present invention, a compound of formula ( I ) or ( II ) has a DNA binding group of formula DB1 . This group contains structures that at least contain a 6-membered ring B linked to a DNA alkylating unit via a fused 5- or 6-membered ring A or a vinyl group. The optimal heteroatom in said B ring may provide improved water solubility compared to DNA binding analogs having a ring consisting of only carbon atoms. In one embodiment, ring B in group DB1 contains a heteroatom.

Preferably, ring B is aromatic. This, for example, can be phenyl, pyridine, pyrimidine, pyridazine, pyrazine, 1,3,5-triazine, 1,2,3,5-tetrazine, 1,2,3,4-tetrazine, pentazine, phosphinine, 1, 3-diphosphinin or 1,3-azaphosphinin group. Alternatively, this ring may be non-aromatic and / or be unsaturated or fully saturated.

A compound of formula ( I ) or ( II ), wherein ring B is linked to a DNA alkylating group via a vinyl group, may contain a convenient group that provides detoxification by, for example, oxidation or hydration of the double bond.

Group DB1 , for example, may be

.

.

DB1 may, for example, also be

.

.

In another embodiment, the group DB1 may be

.

.

In a more specific embodiment, the group DB1 , for example, may be

,

,

where R ^9a has the same meaning as defined for R ⁹ , and is independently selected.

DB1 may, for example, also be

.

.

In typical structures DB1 R ⁸ , R ^{8 '} R ⁹ , R ^9' , R ^9a , R ¹⁰ , R ^{10 '} , R ¹¹ , R ^11' , R ¹⁵ , R ¹⁶ and R ²¹ , for example, each may independently be H, represent or contain another group selected from structures DB1 to DB9, or a derivative thereof, or represent

,

,

where R ⁶² , R ⁶³ , R ⁶⁴ and R ^{65 are} independently selected from H, C _1-3 alkyl, and

,

,

where jj, jj 'and jj''are independently selected from values from 0 to 8, each tt, tt' and tt '' are independently selected from values 0 and 1, each of X ²¹ and X ^{22 is} independently selected from O, S, NR ⁶⁷ , H ₂ and C (R ⁶⁷ ) R ⁶⁸ , where R ⁶⁷ and R ^{68 are} independently selected from H and optionally substituted C _1-3 alkyl or C _1-3 heteroalkyl, and R ⁶⁶ selected from H, COOH, CO ₂ Me , OH, OMe, NR ⁶⁹ R ⁷⁰ , NR ⁶⁹ C (O) CH ₃ , SH, SMe,

,

,

WhereX ²³ selected from halogen, hydroxy, OC (O) R^bb and OC (O) OR^bb, or C (O) -X ²³ is an activated ester,X ²⁴ selected from halide, mesyloxy, triflyloxy and tosyloxy, R^bb selected from optionally substituted C_1-10 alkyl, C_1-10 heteroalkyl, C_3-10 cycloalkyl, C_1-10 heterocycloalkyl, C_5-10 arial and C_1-10 heteroaryl and R⁶⁹, R⁷⁰ and R⁷¹ independently selected from methyl and H.

In a further embodiment, the group DB1 , for example, may be

.

.

another embodiment, the group DB1 , for example, may be

.

.

In another aspect of the present invention, the compound of formula ( I ) or ( II ) contains a DNA binding group of the formula DB2 . This group contains structures that at least contain a 5-membered ring B , which is linked to a DNA alkylating group via a fused 5- or 6-membered ring A or a vinyl group. In particular, in the second case, ring B may be fused to another heterocyclic or carbocyclic aromatic or non-aromatic ring to obtain improved DNA binding affinity. To provide increased water solubility, the fused ring may be a heterocycle or carbocycle substituted with relatively polar groups, which at the same time can provide convenient groups for binding to progroups. A DNA binding agent in which three or more rings are fused together to form an aromatic polycyclic system may be less suitable as it can increase the hydrophobicity and / or tendency to aggregate the DNA binding agent and thus increase the hydrophobicity and / or aggregation tendency compounds of formula ( I ) or ( II ) and its conjugates. This may be especially true for polycyclic aromatic systems in which none is or only one of the ring atoms is a heteroatom.

DB2 DNA binding agent may contain an aromatic core structure. Alternatively, one or more rings may be non-aromatic and may be either unsaturated or fully saturated.

A compound of formula ( I ) or ( II ), wherein ring B is linked to a DNA alkylating group via a vinyl group, may contain a convenient group that provides detoxification by, for example, oxidation or hydration of the double bond.

A DB2 group, for example, may be

where R ^8a , R ^9a , R ^10a and R ^11a have the same meanings as defined for R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ , respectively, and are independently selected.

In a more specific embodiment, the DB2 group, for example, may be

where R ⁷² and R ^{73 are} independently selected from H and methyl.

In typical DB2 structures R ⁸ , R ^8a , R ^9a , R ¹⁰ , R ^10a , R ¹¹ , R ^11a , R ¹⁵ , R ¹⁶ and R ²¹ , for example, each may independently be H, represent or contain another group, selected from structures DB1-DB9, or its derivative, or represent

where R ⁶² , R ⁶³ , R ⁶⁴ and R ^{65 are} independently selected from H, C _1-3 alkyl, and

,

,

where jj, jj 'and jj''are independently selected from values from 0 to 8, each tt, tt' and tt '' are independently selected from 0 and 1, each of X ²¹ and X ^{22 is} independently selected from O, S, NR ⁶⁷ , H ₂ and C (R ⁶⁷ ) R ⁶⁸ , where R ⁶⁷ and R ^{68 are} independently selected from H and optionally substituted C _1-3 alkyl or C _1-3 heteroalkyl, and R ^{66 is} selected from H, COOH, CO ₂ Me, OH, OMe, NR ⁶⁹ R ⁷⁰ , NR ⁶⁹ C (O) CH ₃ , SH, SMe,

,

,

WhereX ²³ selected from halogen, hydroxy, OC (O) R^bb and OC (O) OR^bb, or C (O) -X ²³ is an activated ester,X ²⁴ selected from halide, mesyloxy, triflyloxy and tosyloxy, R^bb selected from optionally substituted C_1-10 alkyl, C_1-10 heteroalkyl, C_3-10 cycloalkyl, C_1-10 heterocycloalkyl, C_5-10 aryl and c_1-10 heteroaryl and R⁶⁹, R⁷⁰ and R⁷¹ independently selected from methyl and H.

In a further embodiment, the DB2 group, for example, may be

In another aspect of the present invention, the compound of formula ( I ) or ( II ) has a DNA binding group of the formula DB3 or DB4 . These two groups contain structures that form an acetylene group linked to a 5- or 6-membered ring. This ring may be aromatic or non-aromatic. In the second case, it can be either unsaturated or fully saturated. In addition, a 5- or 6-membered ring may be fused to one or more other rings to form an aromatic or non-aromatic ring system. Such a ring system is preferably flat since it can increase the affinity of DNA binding. Either polar substituents or heteroatoms in the ring can provide increased water solubility and can have a beneficial effect on the pharmacological properties of the compounds of formula ( I ) or ( II ). The presence of an acetylene group in the DNA binding units of DB3 and DB4 can provide a convenient group that detoxifies through, for example, oxidation or hydration.

DB3 group, for example, may be

DB4 group, for example, may be

.

.

In a more specific embodiment, the DB3 group, for example, may be

.

.

In another more specific embodiment, the DB4 group, for example, may be

,

,

where R ^{72 is} selected from H and methyl.

In typical structures DB3 and DB4 , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ²⁰ , for example, each can be independently selected from H, represent or contain another group selected from structures DB1-DB9 , or a derivative thereof , or represent

where R ⁶² , R ⁶³ , R ⁶⁴ and R ^{65 are} independently selected from H, C _1-3 alkyl, and

,

,

where jj, jj 'and jj''are independently selected from values from 0 to 8, each tt, tt' and tt '' are independently selected from 0 and 1, each of X ²¹ and X ^{22 is} independently selected from O, S, NR ⁶⁷ , H ₂ and C (R ⁶⁷ ) R ⁶⁸ , where R ⁶⁷ and R ^{68 are} independently selected from H and optionally substituted C _1-3 alkyl or C _1-3 heteroalkyl, and R ^{66 is} selected from H, COOH, CO ₂ Me, OH, OMe, NR ⁶⁹ R ⁷⁰ , NR ⁶⁹ C (O) CH ₃ , SH, SMe,

,

,

WhereX ²³ selected from halogen, hydroxy, OC (O) R^bb and OC (O) OR^bb, or C (O) -X ²³ is an activated ester,X ²⁴ selected from halide, mesyloxy, triflyloxy and tosyloxy, R^bb selected from optionally substituted C_1-10 alkyl, C_1-10 heteroalkyl, C_3-10 cycloalkyl, C_1-10 heterocycloalkyl, C_5-10 aryl and c_1-10 heteroaryl and R⁶⁹, R⁷⁰ and R⁷¹ independently selected from methyl and H.

In a further embodiment, the DB3 group, for example, may be

In another embodiment, a DB4 group, for example, may be

.

.

In another aspect of the present invention, the compound of formula ( I ) or ( II ) has a DNA binding group of formula DB5 . This group contains structures that form a 5-membered or 6-membered ring linked to an optionally substituted vinyl group. The 5-membered or 6-membered ring may be aromatic or non-aromatic. In the second case, it can be either unsaturated or fully saturated. Polar substituents or heteroatoms in the ring and / or polar substituents in the vinyl group can provide increased water solubility and have a beneficial effect on the pharmacological properties of the compounds of formula ( I ) or ( II ). Aromatic substituents on the ring or vinyl group can increase the binding affinity. The presence of a vinyl group in the DB5 DNA binding unit can provide a convenient group that detoxifies through, for example, oxidation or hydration.

DB5 group, for example, may be

.

.

In typical DB5 structures, R ^8b , R ^9b and R ¹⁵ , for example, each, can be independently selected from H, represent or contain another group selected from structures DB1-DB9 , or a derivative thereof, or represent

,

,

where R ⁶² , R ⁶³ , R ⁶⁴ and R ^{65 are} independently selected from H, C _1-3 alkyl, and

,

,

where jj, jj 'and jj''are independently selected from values from 0 to 8, each tt, tt' and tt '' are independently selected from 0 and 1, each of X ²¹ and X ^{22 is} independently selected from O, S, NR ⁶⁷ , H ₂ and C (R ⁶⁷ ) R ⁶⁸ , where R ⁶⁷ and R ^{68 are} independently selected from H and optionally substituted C _1-3 alkyl or C _1-3 heteroalkyl, and R ^{66 is} selected from H, COOH, CO ₂ Me, OH, OMe, NR ⁶⁹ R ⁷⁰ , NR ⁶⁹ C (O) CH ₃ , SH, SMe,

,

,

WhereX ²³ selected from halogen, hydroxy, OC (O) R^bb and OC (O) OR^bb, or C (O) -X ²³ is an activated ester,X ²⁴ selected from halide, mesyloxy, triflyloxy and tosyloxy, R^bb selected from optionally substituted C_1-10 alkyl, C_1-10 heteroalkyl, C_3-10 cycloalkyl, C_1-10 heterocycloalkyl, C_5-10 aryl and c_1-10 heteroaryl and R⁶⁹, R⁷⁰ and R⁷¹ independently selected from methyl and H.

In a further embodiment, the DB5 group, for example, may be

In another aspect of the present invention, the compound of formula ( I ) or ( II ) has a DNA binding group of the formula DB6 or DB7 . These two groups contain structures that form two 5- or 6-membered rings that are linked together via a direct single bond. These rings may each independently be aromatic or non-aromatic. In the second case, they can be either unsaturated or fully saturated. In addition, ring B may be condensed with one or more other rings to form an aromatic or non-aromatic ring system, which is preferably flat. This can increase the affinity of DNA binding. Either polar substituents or heteroatoms in one or more rings can provide increased water solubility and can have a beneficial effect on the pharmacological properties of the compounds of formula ( I ) or ( II ).

DB6 group, for example, may be

.

.

DB7 group, for example, may be

,

,

where R ^8a , R ^9a , R ^10a and R ^11a have the same meanings as defined for R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ , respectively, and are independently selected.

In a more specific embodiment, the DB6 group, for example, may be

.

.

In another more specific embodiment, the DB7 group, for example, may be

In typical structures DB6 and DB7, R ⁸ , R ^8a , R ⁹ , R ^9a , R ¹⁰ , R ^10a , R ¹¹ , R ^11a , R ¹⁵ and R ²⁰ , for example, each, can be independently selected from H, represent or contain another group selected from structures DB1-DB9 , or its derivative, or represent

where R ⁶² , R ⁶³ , R ⁶⁴ and R ^{65 are} independently selected from H, C _1-3 alkyl, and

where jj, jj 'and jj''are independently selected from values from 0 to 8, each tt, tt' and tt '' are independently selected from 0 and 1, each of X ²¹ and X ^{22 is} independently selected from O, S, NR ⁶⁷ , H ₂ and C (R ⁶⁷ ) R ⁶⁸ , where R ⁶⁷ and R ^{68 are} independently selected from H and optionally substituted C _1-3 alkyl or C _1-3 heteroalkyl, and R ^{66 is} selected from H, COOH, CO ₂ Me, OH, OMe, NR ⁶⁹ R ⁷⁰ , NR ⁶⁹ C (O) CH ₃ , SH, SMe,

WhereX ²³ selected from halogen, hydroxy, OC (O) R^bb and OC (O) OR^bb, or C (O) -X ²³ is an activated ester,X ²⁴ selected from halide, mesyloxy, triflyloxy and tosyloxy, R^bb selected from optionally substituted C_1-10 alkyl, C_1-10 heteroalkyl, C_3-10 cycloalkyl, C_1-10 heterocycloalkyl, C_5-10 aryl and c_1-10 heteroaryl and R⁶⁹, R⁷⁰ and R⁷¹ independently selected from methyl and H.

In a further embodiment, the DB6 group, for example, may be

In a further embodiment, the DB7 group, for example, may be

In another aspect of the present invention, the compound of formula ( I ) or ( II ) has a DNA binding group of formula DB8 . This group contains structures that form a monocyclic or polycyclic ring system linked to a DNA alkylating group via a methylene group. Preferably, the DB8 group contains a bicyclic ring system. The ring system may be aromatic or non-aromatic. In the second case, it can be either unsaturated or fully saturated. Either polar substituents or heteroatoms in one or more rings can provide increased water solubility and can have a beneficial effect on the pharmacological properties of the compounds of formula ( I ) or ( II ).

DB8 group, for example, may be

где R^8a, R^9a, R^10a и R^11a имеют те же значения, которые определены для R⁸, R⁹, R¹⁰ и R¹¹, соответственно, и выбраны независимо.

where R ^8a , R ^9a , R ^10a and R ^11a have the same meanings as defined for R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ , respectively, and are independently selected.

In typical structures DB8 R ^8a , R ^9a , R ^10a , R ^11a , R ¹⁵ , R ^{15 '} and R ¹⁶ , for example, each can be independently selected from H, represent or contain another group selected from structures DB1-DB9 , or its derivative, or represent

where R ⁶² , R ⁶³ , R ⁶⁴ and R ^{65 are} independently selected from H, C _1-3 alkyl, and

,

,

where jj, jj 'and jj''are independently selected from values from 0 to 8, each tt, tt' and tt '' are independently selected from 0 and 1, each of X ²¹ and X ^{22 is} independently selected from O, S, NR ⁶⁷ , H ₂ and C (R ⁶⁷ ) R ⁶⁸ , where R ⁶⁷ and R ^{68 are} independently selected from H and optionally substituted C _1-3 alkyl or C _1-3 heteroalkyl, and R ^{66 is} selected from H, COOH, CO ₂ Me, OH, OMe, NR ⁶⁹ R ⁷⁰ , NR ⁶⁹ C (O) CH ₃ , SH, SMe,

WhereX ²³ selected from halogen, hydroxy, OC (O) R^bb and OC (O) OR^bb, or C (O) -X ²³ is an activated ester,X ²⁴ selected from halide, mesyloxy, triflyloxy and tosyloxy, R^bb selected from optionally substituted C_1-10 alkyl, C_1-10 heteroalkyl, C_3-10 cycloalkyl, C_1-10 heterocycloalkyl, C_5-10 aryl and c_1-10 heteroaryl and R⁶⁹, R⁷⁰ and R⁷¹ independently selected from methyl and H.

In a further embodiment, the DB8 group, for example, may be

.

.

In another aspect of the present invention, a compound of formula ( I ) or ( II ) has a DNA binding group of formula DB9 . This group contains structures that form a 5-membered ring, which is directly linked by the nitrogen atom of the DNA-alkylating unit through a single bond. The 5-membered ring may be bonded or fused to one or more other rings to form a polycyclic ring system, which is preferably flat. This can increase the affinity of DNA binding. The ring system may be aromatic or non-aromatic. In the second case, it can be either unsaturated or completely saturated. Either polar substituents or heteroatoms in one or more rings can provide increased water solubility and can have a beneficial effect on the pharmacological properties of the compounds of formula ( I ) or ( II ). In one embodiment, the implementation of the group DB9 group contains at least two ring heteroatoms.

DB9 group, for example, may be

where R ^8a , R ^9a , R ^10a and R ^11a have the same meanings as defined for R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ , respectively, and are independently selected.

In typical DB9 structures, R ^8a , R ^9a , R ^10a , R ^11a and R ⁹ , for example, each, independently, may be selected from H, be or comprise another group selected from structures DB1-DB9 , or a derivative thereof, or present

where R ⁶² , R ⁶³ , R ⁶⁴ and R ^{65 are} independently selected from H, C _1-3 alkyl, and

where jj, jj 'and jj''are independently selected from values from 0 to 8, each tt, tt' and tt '' are independently selected from 0 and 1, each of X ²¹ and X ^{22 is} independently selected from O, S, NR ⁶⁷ , H ₂ and C (R ⁶⁷ ) R ⁶⁸ , where R ⁶⁷ and R ^{68 are} independently selected from H and optionally substituted C _1-3 alkyl or C _1-3 heteroalkyl, and R ^{66 is} selected from H, COOH, CO ₂ Me, OH, OMe, NR ⁶⁹ R ⁷⁰ , NR ⁶⁹ C (O) CH ₃ , SH, SMe,

,

,

WhereX ²³ selected from halogen, hydroxy, OC (O) R^bb and OC (O) OR^bb, or C (O) -X ²³ is an activated ester,X ²⁴ selected from halide, mesyloxy, triflyloxy and tosyloxy, R^bb selected from optionally substituted C_1-10 alkyl, C_1-10 heteroalkyl C_3-10 cycloalkyl, C_1-10 heterocycloalkyl, C_5-10 aryl and c_1-10 heteroaryl and R⁶⁹, R⁷⁰ and R⁷¹ independently selected from methyl and H.

In a further embodiment, the DB9 group, for example, may be

.

.

In one embodiment of the present invention, the DB group is DB1 . In another embodiment, the DB group is DB2 . In yet another embodiment, the DB group is DB3 . In yet another embodiment, the DB group is DB4 . In yet another embodiment, the DB group is DB5 . In yet another embodiment, the DB group is DB6 . In yet another embodiment, the DB group is DB7 . In yet another embodiment, the DB group is DB8 . In yet another embodiment, the DB group is DB9 . In another embodiment, the DB group is selected from DB1 , DB2 , DB3 , DB4 , DB5 , DB6, and DB7 . In another embodiment, the DB group is selected from DB1 , DB2 , DB5 , DB6, and DB7 . In a further embodiment, the DB is selected from DB1 , DB2 , DB6, and DB7 . In another additional embodiment, the DB is selected from DB1 and DB2 . In another additional embodiment, the DB is selected from DB6 and DB7 .

In one embodiment, R ⁵ , R ^{5 '} , R ⁶ , R ^6' , R ⁷ and R ^{7 'are} independently selected from H, OH, SH, NH ₂ , N ₃ , NO ₂ , NO, CF ₃ , CN, C (O) NH ₂ , C (O) H, C (O) OH, halogen, R ^e , SR ^e , S (O) R ^e , S (O) ₂ R ^e , S (O) OR ^e , S (O) ₂ OR ^e , OS (O) R ^e , OS (O) ₂ R ^e , OS (O) OR ^e , OS (O) ₂ OR ^e , OR ^e , NHR ^e , N (R ^e ) R ^f , ⁺ N (R ^e ) (R ^f ) R ^g , P (O) (OR ^e ) (OR ^f ), OP (O) (OR ^e ) (OR ^f ), SiR ^e R ^f R ^g , C (O ) R ^e , C (O) OR ^e , C (O) N (R ^e ) R ^f , OC (O) R ^e , OC (O) OR ^e , OC (O) N (R ^e ) R ^f , N (R ^e ) C (O) R ^f , N (R ^e ) C (O) OR ^f and N (R ^e ) C (O) N (R ^f ) R ^g , where R ^e , R ^f and R ^{g are} independently selected from H and optionally substituted (CH ₂ CH ₂ O) _ee CH ₂ CH ₂ X ¹³ R ^e1 , C _1-15 alkyl, C _1-15 heteroalkyl, C _3-15 cycloalkyl, C _1-15 heterocycloalkyl, C _{5- 15} aryl or C _1-15 heteroaryl, where ee is 1-1000, X ^{13 is} selected from O, S and NR ^f1 and R ^f1 and R ^{e1 are} independently selected from H and C _1-3 alkyl, two or more of R ^e , R ^f and R ^{g are} optionally joined by one or more bonds to form one or more optionally substituted carbocycles and / or heterocycles, or R ⁵ + R ^{5 '} and / or R ⁶ + R ^6' and / or R ⁷ + R ^{7 'are} independently selected from = O, = S, = NOR ^e3 , = C (R ^e3 ) R ^e4 and = NR ^e3 , R ^e3 and R ^{e4 are} independently selected from H and optionally substituted C _1-3 alkyl, or R ^{5 ′} + R ^{6 ′} and / or R ^{6 ′} + R ^{7 ′} and / or R ^{7 ′} + R ^{14 ′ are} absent, which gives a double bond between atoms bearing R ^{5 '} and R ^6' , and / or R ^{6 '} and R ^7' , and / or R ^{7 '} and R ^14' , respectively, two or more of R ⁵ , R ^{5 '} , R ⁶ , R ^{6 '} , R ⁷ , R ^7' , R ¹⁴ and R ^{14 'are} optionally joined by one or more bonds to form one or more optionally substituted carbocycles and / or heterocycles.

In another embodiment, R ⁸ , R ^{8 '} , R ⁹ , R ^9' , R ¹⁰ , R ^{10 '} , R ¹¹ , R ^11' , R ¹⁵ , R ^{15 '} , R ^15'' , R ^15''' , R ¹⁶ , R ^{16 '} , R ²⁰ , R ^20' , R ²¹ , R ^{21 '} , R ²² and R ²³ are each independently selected from H, OH, SH, NH ₂ , N ₃ , NO ₂ , NO, CF ₃ , CN, C (O) NH ₂ , C (O) H, C (O) OH, halogen, R ^h , SR ^h , S (O) R ^h , S (O) ₂ R ^h , S (O ) OR ^h , S (O) ₂ OR ^h , OS (O) R ^h , OS (O) ₂ R ^h , OS (O) OR ^h , OS (O) ₂ OR ^h , OR ^h , NHR ^h , N ( R ^h ) R ⁱ , ⁺ N (R ^h ) (R ⁱ ) R ^j , P (O) (OR ^h ) (OR ⁱ ), OP (O) (OR ^h ) (OR ⁱ ), SiR ^h R ⁱ R ^j , C (O) R ^h , C (O) OR ^h , C (O) N (R ^h ) R ⁱ , OC (O) R ^h , OC (O) OR ^h , OC (O) N (R ^h ) R ⁱ , N (R ^h ) C (O) R ⁱ , N (R ^h ) C (O) OR ⁱ and N (R ^h ) C (O) N (R ⁱ ) R ^j , where R ^h , R ⁱ and R ^{j are} independently selected from H and optionally substituted (CH ₂ CH ₂ O) _ee CH ₂ CH ₂ X ¹³ R ^e1 , C _1-15 alkyl, C _1-15 heteroalkyl, C _3-15 cycloalkyl, C _1-15 heterocycloalkyl, C _5-15 aryl or C _1-15 heteroaryl, two or more of R ^h , R ⁱ and R ^{j are} optionally joined by one or more bonds to form one or more optionally substituted carbocycles and / or heterocycles, or R ⁸ + R ^{8 ′} and / or R ⁹ + R ^{9 '} and / or R ¹⁰ + R ^10' and / or R ¹¹ + R ^{11 '} and / or R ¹⁵ + R ^15' and / or R ^{15 ''} + R ^{15 '''} and / or R ¹⁶ + R ^{16 '} and / or R ²⁰ + R ^20' and / or R ²¹ + R ^{21 'are} independently selected from = O, = S, = NOR ^h1 , = C (R ^h1 ) R ^h2 and = NR ^h1 , R ^h1 and R ^{h2 are} independently selected from H and optionally substituted C _1-3 alkyl, two or more of R ⁸ , R ^{8 '} , R ⁹ , R ^9' , R ¹⁰ , R ^{10 '} , R ¹¹ , R ^{11 '} , R ¹⁵ , R ^15' , R ^{15 ''} , R ^{15 '''} , R ¹⁶ , R ^16' , R ²⁰ , R ^{20 '} , R ²¹ , R ^21' , R ²² and R ²³ optionally with are linked by one or more bonds to form one or more optionally substituted carbocycles and / or heterocycles.

In another embodiment, X ^{3 is} not - X ^3a and X ^3b -.

In a further embodiment, if DB is DB2 in the compound of formula ( I ) or ( II ), then X ¹ is O.

In a further embodiment, if DB is DB2 in the compound of formula ( I ) or ( II ) and X ³ is - X ^3a and X ^3b - then X ¹ is O.

Any alternate represented on any ring in DB1 , DB2 , DB3 , DB4 , DB5 , DB6 , DB7 , DB8 and DB9 may either contain another DB1 , DB2 , DB3 , DB4 , DB5 , DB6 , DB7 , DB8 or DB9 group or any other DNA binding group. Such another DB group or DNA binding group may be linked to the first DB group via, for example, an amide or ketone bond.

In one embodiment, the at least one ring in the DNA binding group is aromatic. In another embodiment, the at least one ring system is aromatic. In yet another embodiment, all the rings in the DNA binding group are aromatic or form an aromatic ring system. In yet another embodiment, the DNA binding group contains at least a bicyclic aromatic group.

Substituents R ¹ -R ²³ may contribute to improving the pharmacological properties of the compounds of formula ( I ) or ( II ) or its conjugate, for example, its water solubility. This, for example, can be achieved by selecting one or more of the substituents R ¹ , R ⁵ , R ^{5 '} , R ⁶ , R ^6' , R ⁷ , R ^{7 '} , R ¹⁴ , R ^14' , R ⁸ , R ^{8 '} , R ⁹ , R ^9' , R ¹⁰ , R ^{10 '} , R ¹¹ , R ^11' , R ¹⁵ , R ^{15 '} , R ^15'' , R ^15'' , R ¹⁶ , R ²⁰ , R ^20' , R ²¹ , R ^{21 '} , R ²² and R ²³ in order to contain or represent an oligoethylene glycol or polyethylene glycol group or a triazole group. Alternatively or simultaneously, one or more substituents may contain or be a water soluble group. The presence of a water-soluble group can not only provide increased water solubility, but can also prevent the compound of formula ( I ) or ( II ) from crossing the biological barrier, especially when it is a non-polar barrier, such as a cell membrane. This may be advantageous, especially when the compound of formula ( I ) or ( II ) is delivered to the target cell by pairing with a guide group before it is released from the conjugate, since the compound of formula ( I ) or ( II ) will be able to leave the cell. Even active transfer through, for example, a P-glycoprotein pump, may be (partially) impaired. When a compound of formula ( I ) or ( II ) is prematurely released from the conjugate, for example, into the bloodstream, it may or may not be able to penetrate insignificantly (non-target) cells nonspecifically, since its membrane translocation capabilities may be impaired by the water-soluble group. This can lead to increased selectivity and therefore fewer side effects. Furthermore, in at least some cases, for example, when a water-soluble group is positively charged under physiological conditions, the water-soluble group can also improve DNA binding affinity through suitable electrostatic interactions with negatively charged phosphate groups.

A water-soluble group is a group that confers increased solubility to a compound of formula ( I ) or ( II ) and / or its conjugate. In one embodiment, the water solubility of the water-soluble group-bearing compound of the present invention is increased by more than 100% compared to a compound without said water-soluble group. In other embodiments, the water solubility of the water-soluble group-bearing compound of the present invention is increased by more than 75% or 50% or 25% or 10% compared to a compound without said water-soluble group. A water-soluble group may also help prevent or reduce aggregation of the compounds of the present invention or reduce side effects. Examples of water soluble groups include, but are not limited to, —NH ₂ , —NH—, —NHR ^s , —NR ^s -, —N (R ^s ) (R ^t ), - ⁺ N (R ^s ) (R ^t ) - , - ⁺ N (R ^s ) (R ^t ) (R ^u ), -COOH, -OP (O) (OH) ₂ , -OP (O) (OH) O-, -OP (O) (OR ^s ) O-, -OP (O) (OH) OR ^s , -OP (O) (OR ^s ) OR ^t , -P (O) (OH) ₂ , -P (O) (OH) O-, -P ( O) (OR ^s ) OH, -P (O) (OR ^s ) O-, -P (O) (OR ^s ) (OR ^t ), -OS (O) ₂ OH, -OS (O) ₂ O- , -OS (O) ₂ OR ^s , -S (O) ₂ OH, -S (O) ₂ O-, -S (O) ₂ OR ^s , -OS (O) OH, -OS (O) O- , -OS (O) OR ^s , -S (O) OH, -S (O) O-, -OS (O) -, -S (O) OR ^s , -OS (O) ₂ -, -OS ( O) ₂ R ^s , -S (O) ₂ -, -S (O) ₂ R ^s , -OS (O) R ^s , -S (O) -, -S (O) R ^s , - (OCH ₂ CH ₂ ) _{v '} OH, - (OCH ₂ CH ₂ ) _v' O-, - (OCH ₂ CH ₂ ) _{v '} OR ^s , a sugar group, an oligosaccharide group and an oligopeptide group, or a protonated or deprotonated form thereof, as well as any combination thereof, wherein R ^s, R ^t and R ^u independently sps anes from H and optionally substituted C _1-3 alkyl, two or more of R ^s, R ^t and R ^u are optionally joined by one or more bonds to form one or more carbocycles and / or heterocycles, and v 'is an integer equal to from 2 to 1000. The water-soluble group may be in any position within the substituent or may comprise a whole substituent. A water-soluble group, for example, can be located in any internal position, be part of the main chain, be part of a ring structure, be a functional group suspended from a main chain or ring, or be placed in a position in which a substituent is attached to the remainder of the agent.

In one embodiment, at least one of R ¹ , R ⁵ , R ^{5 ′} , R ⁶ , R ^{6 ′} , R ⁷ , R ^{7 ′} , R ¹⁴ , R ^{14 ′} , R ⁸ , R ^{8 ′} , R ⁹ , R ^{9 '} , R ¹⁰ , R ^10' , R ¹¹ , R ^{11 '} , R ¹⁵ , R ^15' , R ^{15 ''} , R ^{15 '''} , R ¹⁶ , R ^16' , R ²⁰ , R ^{20 '} , R ²¹ , R ^21' , R ²² and R ²³ contains a water-soluble group.

In another embodiment, at least one of R ⁶ , R ⁷ , R ¹⁴ , R ⁸ , R ^9, and R ¹⁰ contains a water soluble group.

In other embodiments, R ⁸ or R ⁹ or R ¹⁰ or R ⁶ or R ⁷ or R ¹⁴ comprise a water-soluble group.

In one embodiment, the water soluble group is a carboxylic acid group.

In another embodiment, the water soluble group is an amino group.

In further embodiments, the water-soluble group is a primary or secondary, or tertiary, or quaternary amino (ammonium) group. In other embodiments, the water-soluble group is a primary or secondary, or tertiary, or quaternary aliphatic amino (ammonium) group.

The compound of formula ( I ) or ( II ) may not have a reactive group included in its structure. On the other hand, as it becomes clear from the above, a reactive group may be present in its structure, which ensures the interaction of the compounds of formula ( I ) or ( II ) with another group. For example, a compound of formula ( I ) or ( II ) can interact with a guiding group or with a linker-targeting group structure, for example, an antibody or antibody fragment, or an antibody-linker structure or an antibody-linker fragment structure, to produce a targeting agent-group conjugate in one or more steps, which may or may not be a conjugate of formula ( III ). The conjugate formation can not only be accomplished by chemical synthesis, but can also occur in situ , i.e. with the introduction of the compounds of formula ( I ) or ( II ) in vivo. A compound of formula ( I ) or ( II ) may, for example, bind to endogenous proteins, for example, albumin, when administered.

Conjugates and conjugates linker-agent

In another aspect, the present invention relates to a conjugate of a compound of formula ( I ) or ( II ), which can be converted in vivo in one or more steps into a compound of formula ( I ) or ( II ), respectively. Also, the conjugate can be converted to a derivative of the compound of formula ( I ) or ( II ), in which part of the progroup attached to the compound of formula ( I ) or ( II ) in the conjugate remains attached to the compound of formula ( I ) or ( II ) after conversion in vivo. An alternative approach is that the remaining linker group is part of a compound of formula ( I ) or ( II ).

These conjugates can have a beneficial effect on the pharmacological properties and other characteristics of the compounds of formula ( I ) or ( II ). In one embodiment, the present invention relates to a conjugate comprising a compound of formula ( I ) or ( II ) coupled to at least one progroup. In another embodiment, the present invention relates to a conjugate comprising a compound of formula ( I ) or ( II ) conjugated to a progroup.

In a further embodiment, the present invention relates to a compound of formula ( III ):

,

,

or its pharmaceutically acceptable salt, hydrate or MES, where

V ² either absent or represents a functional group;

everyoneL ² independently absent or is a linking groupV ² fromL;

each L is independently absent or is a linking group linking L ² to one or more V ¹ and / or Y ;

each V ^{1 is} independently absent or is a group cleaving or transforming under certain conditions, which can be cleaved or transformed by a chemical, photochemical, physical, biological and enzymatic method;

everyoneY independently absent or is a self-breaking spacer system that contains 1 or more self-removing spacers and is associated withV ^one, not necessaryL, and one or moreZ;

each p and q are numbers indicating a degree of branching, and are each, independently, a positive number;

z is a positive number that is equal to or less than the total number of sections joining Z ;

each Z independently represents a compound of formula ( I ), ( II ), ( I ' ) or ( II' ), as defined herein above, where one or more of X ¹ , R ⁵ , R ^{5 '} , R ⁶ , R ^{6 '} , R ⁷ , R ^7' , R ¹⁴ , R ^{14 '} , R ⁸ , R ^8' , R ⁹ , R ^{9 '} , R ¹⁰ , R ^10' , R ¹¹ , R ^{11 '} , R ¹⁵ , R ^{15 '} , R ^15'' , R ^15''' , R ¹⁶ , R ^{16 '} , R ²⁰ , R ^20' , R ²¹ , R ^{21 '} , R ²² and R ²³ optionally, in addition, may be substituted by a Deputy of the formula ( V ) or be a substituent of formula ( V ):

,

,

where each V ^{2 '} , L ^2' , L ' , V ^1' , Y ' , Z' , p ', q' and z 'has the same meaning as defined for V ² , L ² , L , V ¹ , Y , Z , p, q and z, respectively, and independently selected, and wherein one or more substituents of formula ( V ) are independently linked via Y ' to one or more X ¹ , R ⁵ , R ^5' , R ⁶ , R ^{6 '} , R ⁷ , R ^7' , R ¹⁴ , R ^{14 '} , R ⁸ , R ^8' , R ⁹ , R ^{9 '} , R ¹⁰ , R ^10' , R ¹¹ , R ^{11 '} , R ¹⁵ , R ^15' , R ^{15 ''} , R ^{15 '''} , R ¹⁶ , R ^16' , R ²⁰ , R ^{20 '} , R ²¹ , R ^21' , R ²² , R ²³ , and / or with one or more atoms bearing these R substituents;

each Z is independently linked to Y via either X ¹ , an atom in R ⁵ , R ^{5 '} , R ⁶ , R ^6' , R ⁷ , R ^{7 '} , R ¹⁴ , R ^14' , R ⁸ , R ^{8 '} , R ⁹ , R ^{9 '} , R ¹⁰ , R ^10' , R ¹¹ , R ^{11 '} , R ¹⁵ , R ^15' , R ^{15 ''} , R ^{15 '''} , R ¹⁶ , R ^16' , R ²⁰ , R ^{20 '} , R ²¹ , R ^{21 '} , R ²² , R ²³ , or an atom bearing any of these R substituents; and

at least V ² or V ^{1 is} present.

In an additional aspect, the present invention relates to a compound of formula ( III ), where

V ² present and selected as a targeting group, and there is at least one group of the formula (V), which containsV ^one' group, and contains eitherV ^{2 '},L ^{2 '}eitherL ^'' a group that containsX ^fourteen(CH₂CH₂O)_ggCH₂CH₂ X ^fourteen a group where gg is selected from values from 3 to 1000, and each ofX ^fourteen independently selected from

or said same group of formula ( V ) contains at least 2 X ¹⁴ CH ₂ CH ₂ OCH ₂ CH ₂ X ¹⁴ groups in which each of X ^{14 is} independently selected.

From the formula (III) it should be clear thatL may be associated withV ^one and / or withY. IfL associated withYthat means bothV ^one andLas well as one or moreZ, connected withY. IfL associated withV ^one, it means thatV ^one and one or moreZ connected withY.L may also be associated with bothV ^one andY at the same time. IfY absent,L associated withV ^one or ifV ^one absent,L directly related toZ.

V ²(-L ²-L(- (V ^one-Y)))_p)_q(Z)_z-1 and one or moreV ^{2 '}(-L ^{2 '}-L '(- (V ^one'-Y ')))_{p '})_{q '}(Z ')_z'-1 groups whereL(- (V ^one-Y)))_p shows thatL may be associated withV ^one and / or withYrelated toZ are referred to herein as progroups.

The present invention also relates to a compound of formula (IV) :

,

,

or its pharmaceutically acceptable salt, hydrate or MES, where

RM is a reactive group, and L , V ¹ , Y , Z , p and z are as defined hereinabove, except that L in this case binds RM to one or more of V ¹ and / or Y , and V ¹ , Y and Z may contain protective groups, and instead of one or more V ^{2 '} - L ^2' groups optionally present in Z, as defined hereinabove, RM ' , which is reactive group, and where, if more than 1 reactive group is present PPA in (IV) , some or all of the reactive groups are the same or different. These linker-agent conjugates of formula (IV) may or may not be considered as intermediates for compounds of formula ( III ). In the compound of formula (IV), RM must be present, while V ¹ may either be present or absent.

In an additional aspect, the present invention relates to a compound of formula (IV) , wherein RM is a reactive group selected from carbamoyl halide [-N (R) C (O) X], acyl halide [-C (O) X], activated complex ester [-C (O) OR], anhydride [-C (O) OC (O) OR], α-haloacetyl [-C (O) CH ₂ X], α-haloacetamide [-N (R) C (O ) CH ₂ X], maleimide, isocyanate [-N = C = O], isothiocyanate [-N = C = S], disulfide [-S-SR], thiol [-SH], hydrazine [-NH ₂ NH ₂ ] hydrazide [-C (O) NH ₂ NH ₂ ], sulfonyl chloride [-S (O) ₂ Cl], aldehyde [-C (O) H], methyl ketone [-C (O) CH ₃ ], vinyl sulfone [-S (O) ₂ -CH = CH _2], halomethyl [-CH ₂ Cl] and metils lfonata [-CH ₂ OS (O) ₂ R], and wherein at least one group of formula (V), which is part of Z, contain V ^{1 'group,} or contains V ^2', L ^{2 'and L'} group which contains X ¹⁴ (CH ₂ CH ₂ O) _gg CH ₂ CH ₂ X ¹⁴ group, where gg is selected from values from 3 to 1000, and each of X ^{14 is} independently selected from

or said same group of formula ( V ) contains at least 2 X ¹⁴ CH ₂ CH ₂ OCH ₂ CH ₂ X ¹⁴ groups in which each of X ^{14 is} independently selected. These linker-agent conjugates of formula (IV) may or may not be considered as intermediates for compounds of formula ( III ). In such a compound of formula (IV) , RM must be present.

RM-L(- (V ^one-Y)))_p(Z)_z-1 and one or moreRM '-L '(- (V ^one'-Y ')))_{p '}(Z ')_z'-1 fragments whereL(- (V ^one-Y)))_p shows thatL may be associated withV ^one and / or withYrelated toZ designated herein as progroups.

It should be noted that the individual groups X ¹⁴ in the groups —CH ₂ CH ₂ X ¹⁴ that may be present in the compound of formula ( III ) or (IV) are independently selected.

It is also noted that z does not indicate the degree of polymerization; thus, z does not show that a number of groups Z are related to each other.

It is further noted that if Y or Y ′ is bonded to an atom bearing a specific R substituent, and not to the R substituent itself, this actually means that this R substituent is absent if necessary to comply with the valency rules.

, тогда -CH₂CH₂ X ¹⁴ должен читаться как -CH₂CHX ¹⁴.It is further noted that if X ¹⁴ , for example, in -CH ₂ CH ₂ X ¹⁴ represents

then -CH ₂ CH ₂ X ¹⁴ should read like -CH ₂ CH X ¹⁴ .

Note that the present invention relates to enantiomerically pure and / or diastereomerically pure compounds of the formula ( III ) and (IV) , as well as to enantiomeric and / or diastereoisomeric mixtures of the compounds of the formula ( III ) and (IV) .

When a compound of formula ( III ) or (IV) contains attachment points in Y for Z that are not linked to Z , for example, as a result of a coupling reaction with Z incomplete during the synthesis, these attachment points are believed to carry H instead. OH or a deleted group. If all of the indicated attachment points are associated with Z , then z is equal to the number of the indicated attachment points; otherwise, z is equal to a smaller number. The compounds of the present invention may be in the form of a mixture in which each component of the mixture has a different z value. For example, the compound may be in the form of a mixture of two separate compounds, one compound where z is 4 and another compound where z is 3. In addition, for a given z, the compound may be in the form of a mixture of (structural) isomers, since Z can be connected to individual (group) attachment points.

For clarity, when referring to the relationship of one first group with other groups in the formula (III) or(Iv)usually only those groups are indicated that are directly attached to the first group in the formula (III) or(Iv). It should be noted that if one of the indicated other groups is not present, the specified first group is actually connected to the group, the first in the line, which is present, unless clearly indicated otherwise. For example, if it says "V ^one split offY", this phrase actually means"V ^one split offY orZ ifY missing "and should read like"V ^one split offZ"when the link is made to the connection withoutY.

In a compound of formula ( III ) or (IV), Z can be conjugated to a progroup through a water-soluble group thereof, for example, an oligoethylene glycol or polyethylene glycol group. Thus, a water-soluble group may contribute to a lesser extent the water solubility of the compounds of formula ( III ) or (IV) , but may again contribute to the water solubility of Z after removal of said progroup.

Whenever V ² , L ² , L , V ¹ , Y , Z , RM , p, q or z is indicated in this document, it should be noted that the same may be applicable for each V ^{2 '} , L ^2' , L ' , V ^1' , Y ' , Z' , RM ' , p', q 'or z', respectively, unless otherwise indicated in the context.

V ^one Group

In a compound of formula ( III ) or (IV), group V ¹ is a group that is conditionally cleavable or convertible. In other words, it was obtained so that it could be transformed and / or split off from Y in a chemical, photochemical, physical, biological or enzymatic manner, being placed under certain conditions or under certain conditions. These conditions, for example, can be placing the compound of the invention in an aqueous medium, which leads to the hydrolysis of V ¹ , or placing the compound of the invention in a medium that contains an enzyme that recognizes and cleaves V ¹ , or placing the compound of the invention in reducing conditions, which leads to the restoration and / or removal of V ¹ , or placing the compound according to the invention in oxidizing conditions, which leads to the restoration and / or removal of V ¹ , or placing the compound according to the invention in contact with radiation, for example, UV radiation, which leads to conversion and / or cleavage, or placing the compound of the invention in contact with heat, which leads to the conversion and / or cleavage, or placing the compound of the invention under reduced pressure conditions, which leads to conversion, for example, retrocycloaddition and / or cleavage or placing the compound of the invention under elevated or high pressure conditions, resulting in conversion and / or cleavage. These conditions can be achieved after administration of the compound of the present invention to an animal, for example, a mammal, for example, a human: a condition can be provided when the compound is localized, for example, in a specific organ, tissue, cell, intracellular target, or bacterial, viral or microbial target , for example, by the presence of internal factors (e.g., target-specific enzymes or hypoxia) or by the use of external factors (e.g., radiation, magnetic fields), or the condition can already be provided directly upon administration (for example, ubiquitous enzymes in the bloodstream).

Cleavage of V ¹ means that the connection between V ¹ and Y is broken. The transformation of V ¹ means that V ^{1 is} transformed into another group, and this transformation can directly or indirectly lead to self-cleavage of V ¹ from Y. Alternatively, the V ¹ transformation can lead to the formation of a V ¹ - Y group, which is a self-removing linker. In this case, Y only becomes self-deleting after the transformation V ¹ . The transformed group V ¹ actually becomes (partially) part of Y. For example, oxidation of V ¹ , which is a hydrogen atom, to a hydroxyl group can lead to the formation of a self-destructive para- or ortho- hydroxybenzyloxycarbonyl group V ¹ - Y. As another example, the reduction of V ¹ , which is a nitro group, can lead to the formation of a self-destructive para- or ortho- aminobenzyloxycarbonyl V ¹ - Y group.

Alternatively, in turn, V ¹ may be absent. In this case, the progroup is not removable from Z, and the whole progroup or part thereof (in the case of the decomposition of a compound of formula ( III ) or (IV) at one or more other sites in the molecule) will remain associated with one or more Z groups. One of the alternative ways to address this issue is that the part of the progroup that remains attached to group Z is actually part of group Z.

The compound of the present invention may contain more than one V ¹ group per progroup (p and / or q> 1). These V ¹ groups may or may not be the same and may or may not need the same conditions for conversion and / or cleavage.

In one aspect of the present invention, a conjugate is used to target one or more Z fragments to target cells. In this case, the group V ¹ may, for example, contain a substrate of the molecule, which is cleaved using an enzyme located next to the target cell or inside the target cell, for example, tumor cells. V ¹ may, for example, contain a substrate that is cleaved by an enzyme located at high levels next to or inside the target cell compared to other parts of the body, or by an enzyme that is present only next to or inside the target cell.

It is important to recognize that if the specificity of the target site is achieved solely depending on the selective conversion and / or cleavage of said V ¹ at the target site, the cleavage condition should preferably be at least to a certain extent specific to the target site, whereas the presence of another specifically targeted group in the compound of the invention, for example, in group V ² , weakens or eliminates this requirement. For example, when V ² induces selective internalization in a target cell, an enzyme also present in other cells can transform and / or cleave V ¹ . However, cleavage should not preferably occur at a site remote from the target site. Thus, the conjugate should not be exposed to enzymes or conditions that could cause cleavage of V ¹ at sites other than the target site. In one embodiment, the conversion and / or cleavage of V ¹ occurs intracellularly. In another embodiment, the conversion and / or cleavage of V ¹ occurs extracellularly. In another embodiment, the conversion and / or cleavage of V ¹ occurs using a ubiquitous intracellular enzyme. In another embodiment, the conversion and / or cleavage of V ¹ occurs using a ubiquitous extracellular enzyme.

In one embodimentV ^one contains an amino acid, di-, tri-, tetra- or oligopeptide, or peptidomimetic, which consists of an amino acid or amino acid sequence or its mimetic, recognized and cleaved by a proteolytic enzyme, for example, plasmin, cathepsin, cathepsin B, specific prostatic antigen (PSA), an urokinase type plasminogen activator (u-PA), or a member of the matrix metalloproteinase family located next to or inside target cells, for example, tumor cells. In one embodimentV ^one represents peptide. In another embodimentV ^one is a single amino acid. In another embodimentV ^one represents dipeptide. In another embodimentV ^one represents tripeptide. In another embodimentV ^one represents tetrapeptide. In yet another embodimentV ^one is a peptidomimetic.

In another embodiment, V ¹ contains β-glucuronide, which is recognized by β-glucuronidase located adjacent to or within the tumor cells.

In one embodiment, V ¹ contains a substrate for the enzyme.

In one embodiment, V ¹ comprises a substrate for an extracellular enzyme.

In another embodiment, V ¹ contains a substrate for an intracellular enzyme.

In yet another embodiment, V ¹ comprises a substrate for the lysosomal enzyme.

In yet another embodiment, V ¹ comprises a substrate for a plasmin of the serine protease family.

In yet another embodiment, V ¹ contains a substrate for one or more cathepsins, for example, cathepsin B.

In yet another embodiment, V ¹ comprises a substrate for galactosidase.

In yet another embodiment, V ¹ comprises a substrate for NQO1 quinone reductase.

In yet another embodiment, V ¹ contains a hydrazide, hydrazone, or an imine group that is to be intracellularly hydrated.

In yet another embodiment, V ¹ contains a disulfide group that must be cleaved intracellularly.

When V ^{1 is} cleaved extracellularly, one or more Z groups can be released extracellularly. This may provide an advantage in the sense that these Z groups are not only able to influence the cells directly surrounding the activation site (e.g., target-positive cells), but also to cells located quite far from the activation site (e.g., target-negative cells) due to diffusion (witness effect), provided that Z groups are able to penetrate cell membranes.

The enzyme for the removal of V ¹ can also be moved to the area near the target cell or into the target cell or to the target tissue by, for example, antibody-directed enzymatic prodrug therapy (ADEPT), polymer-directed enzymatic prodrug therapy (PDEPT), macromolecular directed enzymatic prodrug therapy (MDEPT), virus directed enzymatic prodrug therapy (VDEPT), or gene directed enzymatic prodrug therapy (GDEPT). In these methods, the enzyme that must cleave V ¹ is transferred or introduced in order to be obtained at the target site before the administration of a drug, for example, a compound of formula ( III ) or (IV) . In one embodiment, the conversion and / or cleavage of V ¹ occurs through an enzyme associated with an antibody using an ADEPT approach.

In another embodiment, V ¹ contains a group, for example, a nitrobenzyl group, which can be transformed and / or cleaved by reduction under hypoxia or by reduction with nitroreductase. After restoration of the nitro group and cleavage of the obtained group by self-destruction, self-destruction of the spacer system Y , if any, leads to the release of one or more groups in Z.

In one embodiment, the invention relates to a conjugate, whereinV ^one represents a single amino acid, dipeptide, tripeptide, tetrapeptide or oligopeptide group containing natural L-amino acids, unnatural D-amino acids, or synthetic amino acids or peptidomimetics, or any combination thereof.

In another embodiment, the invention relates to a compound wherein V ¹ contains a tripeptide. The tripeptide may be linked at its C-terminus to Y. In one embodiment, the C-terminal amino acid residue of the tripeptide is selected from alanine, arginine, citrulline and lysine, the average amino acid residue of the tripeptide is selected from alanine, valine, leucine, isoleucine, methionine, phenylalanine, cyclohexylglycine, tryptophan and proline, and the N-terminal amino acid the tripeptide residue is selected from any natural or unnatural amino acid.

In another embodiment, the invention relates to a compound wherein V ¹ contains a dipeptide. The dipeptide may be linked at its C-terminus to Y. In one embodiment, the C-terminal amino acid residue of the dipeptide is selected from alanine, arginine, citrulline and lysine, and the N-terminal amino acid residue of the dipeptide is selected from any natural or unnatural amino acid.

In yet another embodiment, the invention relates to a compound wherein V ¹ contains a single amino acid. An amino acid may be linked to Y via its carboxyl group. In one embodiment, the amino acid is selected from alanine, arginine, citrulline and lysine.

In one embodiment, when the α-amino group in the N-terminal amino acid in V ^{1 is} not linked to L , this amino acid can be functionalized with a suitable blocking group linked to the α-amino group, or it can be a non-natural amino acid in such a way that undesired premature the destruction of V ¹ using, for example, ubiquitous enzymes, for example, exopeptidases.

In a further embodiment, V ¹ is selected from D-alanilfenilalanillizina, D-valilleytsillizina, D-alanilleytsillizina, D-valilfenilalanillizina, D-valiltriptofanillizina, D-alaniltriptofanillizina, alanilfenilalanillizina, valilleytsillizina, alanilleytsillizina, valilfenilalanillizina, valiltriptofanillizina, alaniltriptofanillizina, D-alanilfenil-alaniltsitrullina, D-valleleylcylcytrulline, D-alanylleucylcytrulline, D-valylphenylalanylcytrulline, D-valyl-tryptophanylcytrulline, D-alanyl tryptophanylcytrulline, alanylphenylalanylcytriline Ulline, valleylcylcytrulline, alanyllecylcytrulline, valylphenylalanylcytrulline, valyltryptophanylcytrulline and alanyl tryptophanylcytrulline.

In another embodiment, V ¹ is selected from fenilalanillizina, valillizina, valilalanina, D-fenilalanilfenilalanillizina, fenilalanilfenilalanillizina, glitsilfenilalanillizina, alanillizina, valiltsitrullina, N-metilvaliltsitrullina, fenilalaniltsitrullina, izoleytsiltsitrullina, triptofanillizina, triptofaniltsitrullina, fenilalanilarginina, fenilalanilalanina, glitsilfenilalanilleytsilglitsina, alanilleytsilalanilleytsina, alanilarginilarginina, phenylalanyl -N -tozilarginina ^9, phenylalanyl-N ⁹ -nitroarginina, leytsillizina, leytsiltsitr Llyn and phenylalanyl-O-benzoiltreonina.

In a further embodiment, V ^{1 is} selected from phenylalanillisine, valillisine, and valicitrulline.

Thus, in one embodiment, the present invention relates to a compound whereinV ^one contains a substrate that can be cleaved by a proteolytic enzyme, plasmin, cathepsin, cathepsin B, β-glucuronidase, specific prostatic antigen (PSA), an urokinase-type plasminogen activator (u-PA), a member of the matrix metalloproteinase family, or an enzyme localized a prodrug therapy enzyme such as ADEPT, VDEPT, MDEPT, GDEPT or PDEPT, or whereV ^one contains a group that can be cleaved or transformed by reduction under hypoxic conditions, by reduction with nitroreductase, or by oxidation.

In another aspect of the present invention, the conjugate of the present invention is mainly used to improve the pharmacological properties of Z. When the progroup must not be selectively deleted at the target site, V ¹ in the specified progroup, for example, may either contain a group that is cleaved by ubiquitous enzymes, such as esterase, which are present in the bloodstream or intracellular enzymes, such as, for example, proteases and phosphatases by pH-controlled intramolecular cyclization or by acid-catalyzed, base-catalyzed or non-catalyzed hydrolysis, or V ¹ , for example, can either contain disulfide or form disulfide with an adjacent group. Thus, V ¹ may optionally form together with the bonding atom (s) in L and / or Y , for example, carbonate, carbamate, urea, ester, amide, imine, hydrazone, hydrazide, oxime, disulfide, acetal, or a ketal group that can be cleaved in vivo. This means that V ¹ , optionally together with the bonding atom (s) of the atom (s) in L and / or Y , can also be, for example, -OC (O) -, -C (O) O-, -OC ( O) O-, -N (R ^v ) C (O) -, -C (O) N (R ^v ) -, -N (R ^v ) C (O) O-, -OC (O) N (R ^v ) -, -N (R ^v ) C (O) N (R ^w ) -, -C (O) -, -OC (R ^v ) (R ^w ) -, -C (R ^v ) (R ^w ) O-, -OC (R ^v ) (R ^w ) O-, -C (R ^v ) (R ^w ) -, -S-, -SS-, -C =, = C-, -N =, = N -, -C = N-, -N = C-, -ON =, = NO-, -C = NO-, -ON = C-, -N (R ^v ) -N =, = NN (R ^v ) -, -N (R ^v ) -N = C- or -C = NN (R ^v ) -, where R ^v and R ^{w are} independently selected from H and optionally substituted C _1-10 alkyl, C _1-10 heteroalkyl, C _1-10 heteroaryl, C _3-10 cycloalkyl, C _1-10 heterocycloalkyl or C _5-10 aryl, R ^v and R ^w are optionally joined by one or more bonds to form od th or more optionally substituted carbocycles and / or heterocycles.

V ¹ , thus, for example, may or may contain, optionally together with the bonding atom (s) in L and / or Y , a peptide, amino acid, peptidomimetic, disulfide, monosaccharide or disaccharide or its derivative, nitroaromatic group, imine hydrazide or hydrazone group.

If V ¹ or V ¹ - Y represents an entire progroup or L is linked to Y rather than V ¹ , V ¹ , for example, can also be selected from mono-, di- or oligosaccharide, R ^p - [O (R ^{p '} O) P (O)] _pp -, R ^p -C (O) -, R ^p -OC (O) - and R ^p -N (R ^p' ) C (O) -, where pp is selected from 1 to 3 and each R ^p and R ^{p ′ are} independently selected from H and optionally substituted C _1-15 alkyl, C _1-15 heteroalkyl, C _3-15 cycloalkyl, C _1-15 heterocycloalkyl, C _5-15 aryl, or C _1-15 heteroaryl, R ^p and R ^{p 'are} optionally joined by one or more bonds to form one or more optionally substituted carbocycles and / or heterocycles.

In one embodiment, V ^{1 is} selected from phosphono, phenylaminocarbonyl, 4- (piperidin-1-yl) piperidin-1-ylcarbonyl, piperazin-1-ylcarbonyl, piperidin-1-ylcarbonyl, pyrrolidin-1-ylcarbonyl and 4-methylpiperazine 1-ylcarbonyl.

V ¹ as such may contribute to the appropriate pharmacological properties of the conjugate, for example, through the presence of polar functional groups in V ¹ .

If the conjugate of the present invention contains more than 1 progroup, one of these progroups can be used to target the conjugate to the target site (target progroup), while the other progroup is used to improve pharmacological properties. In this case, the group V ¹ in the guide progroup is preferably cleaved at the target site, for example, through a specific targeting process at the site, such as enzymatic cleavage using an enzyme predominantly present on the target site, or through another genetic intracellular process that can only occur after selective internalization of the target cell of the conjugate, while the progroup that improves the pharmacological properties can be split or at the site ishena, or systemically, for example, with the help of ubiquitous enzymes.

It should be noted that V ¹ , either in the form of an amino acid, di-, tri-, tetra- or oligopeptide, or in any other form, may contain protecting groups. Compounds of the invention containing such protected V ¹ may not release any Z group when placed under conditions in which the corresponding unprotected V ¹ is converted and / or cleaved. However, when these compounds are unprotected, such compounds will release one or more Z groups when they are in the appropriate conditions. Compounds containing such protected V ¹ are also included within the scope of the present invention. In particular, the foregoing may be provided for compounds of formula (IV) . Suitable protecting groups for functional groups, in particular amino acids, are well known to those skilled in the art of organic chemistry, and can be found, for example, in TW Greene, Protective Groups in Organic Synthesis , John Wiley & Sons, New York, 1981.

Compounds of Formulas (III) and(Iv) can be obtained, ultimately, for the release of compounds of formula (I) or (II) or a compound of the formula (I ') or (II ') after conversion and / or cleavage of one or moreV ^one andV ^one' groups. The release of the compounds of formula (I) or (II), compounds of the formula (I ') or (II ') or its derivative (for example, due to only incomplete cleavage of the progroup) from the conjugate of the present invention by another mechanism, however, is not excluded from the present invention.

In another aspect of the present invention, a compound of formula (III) is an intermediate to produce a compound of formula (I) or (II), or another compound of the formula (III) In this case, for example,V ²,L ²,L andY are absent, p, q and z are all equal to 1, and the groupV ^one may be a protected group. One or more groupsV ^{2 '}(-L ^{2 '}-L '(- (V ^one'-Y ')))_{p '})_{q '}(Z ')_z'-1 may or may not be present, whereV ^{2 '},L ^{2 '},L ' andY ' may be absent or may be present, and each p ', q' and z 'may or may not be equal to 1. In one embodiment, a compound of formula (III) is a compound of the formula (I) or (II) to which it is attached GroupV ^one. In another embodiment, a compound of formula (III) is a compound of the formula (I) or (II) to which are attached GroupV ^one and groupV ^{2 '}(-L ^{2 '}-L '(- (V ^one'-Y ')))_{p '})_{q '}(Z ')_z'-1. In yet another embodiment, a compound of formula (III) is a compound of the formula (I) or (II) to which are attached GroupV ^one and groupV ^one'.

In one embodimentV ^one not a protecting group.

In another embodiment, V ² , L ² , L and Y are absent, and each p, q and z is 1.

In a further embodimentV ^one represents a chemically removable group.

In another embodimentV ^one is a chemically removable group associated withZ throughX ^one.

In another further embodimentV ^one represents a benzyl group associated withZ throughX ^one.

In another embodiment, V ¹ is tert- butoxycarbonyl (methylamino) ethyl (methylamino) carbonyl.

In another embodiment, V ¹ is 4- ( tert- butoxycarbonyl) piperazine-1-carbonyl.

In one embodimentV ^one associated withL through more than one functional group onV ^one.

In another embodimentV ^one associated withL through one functional group onV ^one.

In another embodimentV ^one associated withL through a functional group in the side chain of one of the natural or unnatural amino acids inV ^one.

In another embodiment, the N-terminal amino acid in V ¹ is linked through its α amino group to L.

In another embodiment, V ^{1 is} absent.

Self Destructible Spacer System Y

A self-destructible spacer system Y , if present, binds V ¹ and optionally L to one or more Z groups.

The self-destructible spacer system Y can be included in the conjugate of the present invention, for example, to improve the properties of Z or the conjugate in general, to improve the chemistry of the corresponding binding and / or to create a space between V ¹ and Z.

The compound of the present invention may contain more than one spacer system Y per progroup. These Y groups may or may not be the same.

After cleavage or transformation of V ¹ , the left side of Y can become unlocked or a self-destructible group V ¹ - Y can be formed, which leads to the possible release of one or more Z groups. Self-destructible spacer systems can, for example, be described in WO 02/083180 and WO 2004/043493, which are incorporated herein by reference in their entirety, as well as other self-destructible spacers known to one skilled in the art.

In one aspect, the invention relates to compounds wherein Y is

( W -) _w ( X -) _x ( A- ) _s ,

Where

W and X are each a spacer of a single-released 1.2 + 2 n electronic cascade ( n ≥1) that are the same or different;

A is an ω-amino aminocarbonyl cyclization spacer that forms a cyclic urea derivative upon cyclization;

s is 0 or 1;

w and x are numbers indicating the degree of polymerization and are, independently, an integer of 0 (inclusive) to 5 (inclusive).

In accordance with another embodiment of the present invention, the spacers 1,2 + 2 n of the electronic cascade W and X independently represent a group having the formula:

Where

Q 'is selected from —R ¹¹⁰ C = CR ¹¹¹ -, S, O, NR ¹¹¹ , —R ¹¹¹ C = N— and —N = CR ¹¹¹ -;

B is selected from NR ¹¹² , O, and S;

P represents C (R ¹⁰⁸ ) (R ¹⁰⁹ ) Q ;

R ¹⁰⁶ , R ¹⁰⁷ , B and ( T -) _t ( T ' -) _t' ( T '' - ) _{t ''} P are associated with C ^a , C ^b , C ^c and C ^d such that B and ( T -) _t ( T ' -) _t' ( T '' - ) _{t ''} P are bonded to two adjacent carbon atoms or to C ^a and C ^d , respectively;

Q is absent or is —OC (O) -;

t, t 'and t' 'are numbers showing the degree of polymerization, and are independently an integer from 0 (inclusive) to 5 (inclusive);

T , T ' and T''are independently selected from groups having the formula:

R ¹⁰⁶ , R ¹⁰⁷ , R ¹⁰⁸ , R ¹⁰⁹ , R ¹¹⁰ , R ¹¹¹ , R ¹¹² , R ¹¹³ and R ^{114 are} independently selected from H, OH, SH, NH ₂ , N ₃ , NO ₂ , NO, CF ₃ , CN , C (O) NH ₂ , C (O) H, C (O) OH, halogen, R ^y , SR ^y , S (O) R ^y , S (O) ₂ R ^y , S (O) OR ^y , S (O) ₂ OR ^y , OS (O) R ^y , OS (O) ₂ R ^y , OS (O) OR ^y , OS (O) ₂ OR ^y , OR ^y , NHR ^y , N (R ^y ) R ^y1 , ⁺ N (R ^y ) (R ^y1 ) R ^y2 , P (O) (OR ^y ) (OR ^y1 ), OP (O) (OR ^y ) (OR ^y1 ), C (O) R ^y , C ( O) OR ^y , C (O) N (R ^y1 ) R ^y , OC (O) R ^y , OC (O) OR ^y , OC (O) N (R ^y ) R ^y1 , N (R ^y1 ) C ( O) R ^y , N (R ^y1 ) C (O) OR ^y and N (R ^y1 ) C (O) N (R ^y2 ) R ^y , where R ^y , R ^y1 and R ^{y2 are} independently selected from H and optionally substituted (CH ₂ CH ₂ O) _ee CH ₂ CH ₂ X ¹³ R ^e1 , C _1-20 alkyl, C _1-20 heteroalkyl, C _3-20 cycloalkyl, C _1-20 heterocycloalkyl, C _5-20 aryl or C _{1- 20} heteroaryl, where ee is 1-1000, X ^{13 is} selected from O, S and NR ^f1 , and R ^f1 and R ^{e1 are} independent may be selected from H and C _1-3 alkyl, two or more R ^y , R ^y1 and R ^{y2 are} optionally joined by one or more bonds to form one or more optionally substituted carbocycles and / or heterocycles, two or more substituents R ¹⁰⁶ , R ¹⁰⁷ , R ¹⁰⁸ , R ¹⁰⁹ , R ¹¹⁰ , R ¹¹¹ , R ¹¹² , R ¹¹³ and R ^{114 are} optionally joined by one or more bonds to form one or more optionally substituted carbocycles and / or heterocycles.

In the above formula, Q may be OC (O), but may also be absent. For example, a compound with a benzyl ether bond between a self-destructible spacer and a group that is removed where the hydroxycarbonyl group is thus absent ( Q is absent) has been reported to undergo self-destruction ⁹ .

According to another embodiment of the invention, the ω-amino aminocarbonyl cyclization disruption spacer A is a group having the formula:

,

,

Where

u is an integer equal to 0 or 1;

R ¹¹⁵ and R ^{116 are} independently selected from H and optionally substituted C _1-6 alkyl;

R ¹¹⁷ , R ¹¹⁸ , R ¹¹⁹ , R ¹²⁰ , R ¹²¹ and R ^{122 are} independently selected from H, OH, SH, NH ₂ , N ₃ , NO ₂ , NO, CF ₃ , CN, C (O) NH ₂ , C (O) H, C (O) OH, halogen, R ^z , SR ^z , S (O) R ^z , S (O) ₂ R ^z , S (O) OR ^z , S (O) ₂ OR ^z , OS (O) R ^z , OS (O) ₂ R ^z , OS (O) OR ^z , OS (O) ₂ OR ^z , OR ^z , NHR ^z , N (R ^z ) R ^z1 , ⁺ N (R ^z ) ( R ^z1 ) R ^z2 , P (O) (OR ^z ) (OR ^z1 ), OP (O) (OR ^z ) (OR ^z1 ), C (O) R ^z , C (O) OR ^z , C (O) N (R ^z1 ) R ^z , OC (O) R ^z , OC (O) OR ^z , OC (O) N (R ^z ) R ^z1 , N (R ^z1 ) C (O) R ^z , N (R ^z1 ) C (O) OR ^z and N (R ^z1 ) C (O) N (R ^z2 ) R ^z , where R ^z , R ^z1 and R ^{z2 are} independently selected from H and optionally substituted (CH ₂ CH ₂ O) _ee CH ₂ CH ₂ X ¹³ R ^e1 , C _1-20 alkyl, C _1-20 heteroalkyl, C _3-20 cycloalkyl, C _1-20 heterocycloalkyl, C _5-20 aryl or C _1-20 heteroaryl, where ee is 1-1000 , X ^{13 is} selected from O, S and NR ^f1 , and R ^f1 and R ^{e1 are} independently selected from H and C _1-3 alkyl, two or more of R ^z , R ^z1 and R ^{z2 are} optionally connected by one or more bonds to form one or more optionally substituted carbocycles and / or heterocycles, two or more of the substituents R ¹¹⁵ , R ¹¹⁶ , R ¹¹⁷ , R ¹¹⁸ , R ¹¹⁹ , R ¹²⁰ , R ¹²¹ and R ^{122 are} optionally joined by one or more bonds to form one or more optionally substituted carbocycles and / or heterocycles.

Cyclization linker A , for example, may be selected from

.

.

In a more specific embodiment, cyclization linker A may be selected from

.

.

In one embodiment, Y is absent.

In another embodiment, the present invention relates to a compound of formula ( III ) or (IV) , wherein X ¹ is O and Y is linked to X ¹ via an ω-amino aminocarbonyl cyclization spacer that is part of Y.

In one embodiment, the spacer system Y is selected from

.

.

In another embodiment, the spacer system Y is

.

.

In another embodiment, the spacer system Y is

Other examples of self-destructible spacers include, but are not limited to, other spacers that may undergo cyclization ¹⁰ , such as optionally substituted 4-aminobutyric acid amides, appropriately substituted bicyclo [2.2.1] and bicyclo [2.2.2] ring systems, amides 2-aminophenylpropionic acid and trimethyl-closing cyclization spacers ¹¹ . A glycine spacer in which the amino-containing leaving group is linked at the α-position is another useful spacer for the compounds of the invention ¹² .

In the conjugate of the present invention, the spacer system Y may be associated with more than one V ¹ group. In this case, the conversion and / or cleavage of one of these V ¹ groups can trigger the release of one or more Z groups. When V ¹ groups that are converted or cleaved under various conditions are bound to the same Y , the release of one or more Z groups can occur when the conjugate of the present invention is placed under one of several different conditions, if Y can undergo self-destruction in various ways. Alternatively, you can use the spacer system Y, which is necessary to run, twice or even more times, self-destruction. An example of such a self-destructible spacer is the bicin spacer ¹³ . When such a spacer is used in combination with other selectively cleavable V ¹ groups associated with said spacer, the release selectivity of Z can be enhanced since two different conditions must be met before Z is released.

Linking group L

Linking groupL links one or more groupsV ^one and / orY fromL ² orRM. Synthesis may be easier whenL associated withV ^one insteadY and the compound may be less prone to premature failure, sinceV ^one may be more secure. BindingL fromY may have an advantage in the sense thatV ^one can more easily be converted and / or cleaved. Other reasons for bindingL fromY may, for example, be that (part)Y remains connectedL when splittingV ^onethat prevents the release of reactive low molecular weight compounds, and that the compound may exhibit improved pharmacological properties, solubility or aggregation parameters.L may be absent, which means thatV ^one orY directly related to or withL ² ,or withRM. However, in another aspectL represents a linking group that functionally binds or places in space one or more groupsV ^one and / orY andL ² or groupRM. In the compound of the formula(Iv) placement in space can make a reactive groupRM more accessible to the reaction partner, for example, when a functional groupV ² connected. In the compound of the formula (IIIa) placement in space may provide better accessibilityV ^one, insofar asV ² is even further, which, in particular, in the case of enzymatic cleavage or transformationV ^one, can increase the speed at whichV ^one converted and / or cleaved.

Linking groupL must contain suitable functional groups at both ends to provide selective binding to one or more groupsV ^one and / orY andL ² orRM.

The linking group L may be a water-soluble group or contain one or more water-soluble groups, so that L promotes the water solubility of the compounds of formula ( III ) or (IV) . L may also be a group or contain one or more groups, which (s) reduces the aggregation of a compound of formula ( III ) or (IV) , which may or may not be a group / fragments, which (s) also increase (s) a) the solubility of the compounds of formula ( III ) or (IV) . Group L may contain an oligoethylene glycol or polyethylene glycol group or a derivative thereof. This group may, for example, improve water solubility and / or reduce aggregation of the compounds of formula ( III ) or (IV) .

In one aspect, the L group is a linear, branched or dendritic group so that it can be associated with one or more of the groups V ¹ and / or Y. Branching can occur through one or more cyclic structures or at one or more branching atoms, which may, for example, be carbon, nitrogen, silicon or phosphorus.

Number of branches inLwhich are related toV ^one and / orYcertainly not equal to the total number of branches, because in the binding reaction withV ^one and / orYnot all branches can be associated with groupsV ^one and / orY due to incomplete chemical conversion. It means thatLcan contain branches that are not relatedV ^one orYbut instead, end in, for example, a functional group, H, OH, or a leaving group.

Thus, when L is branched, the compounds of the present invention can exist as a mixture, where each component of the mixture has a different p value. For example, a compound may exist as a mixture of two separate compounds, one compound where p is 2 and the other compound where p is 3. In addition, for a given p, the compound may exist as a mixture of (structural) isomers, since V ¹ and / or Y may be associated with different (groups) branches on L.

In one embodiment, L is absent.

In another embodiment, L is a linear linker.

In another embodiment, L is a linear linker containing a 1,2,3-triazole group. Such a linker can be formed by a cycloaddition reaction between a molecule containing an azide group and one containing an acetylene group.

In another embodimentLrepresents branched linker.

In another embodiment, L is a dendritic linker. A dendritic structure, for example, can be formed by a cycloaddition reaction between molecules containing one or more azide groups and containing one or more acetylene groups.

In one embodiment, p is 1.

In other embodiments, p is 2 or 3, or 4, or 6, or 8, or 9.

In another embodiment, L is represented by the formula:

,

,

Where

X ¹⁰¹ andX ¹⁰² represent, each, independently, O, NR¹³¹ or S;

each of X ¹⁰³ and X ¹⁰⁴ is independently O, NR ¹³² or S;

each of xa, xb, xc and xd is independently 0 or 1;

kk is equal to a number representing the degree of branching, and is an integer from 1 (inclusive) to 128 (inclusive);

ll is equal to a number representing the degree of branching, and is an integer from 0 (inclusive) to 127 (inclusive);

kk + ll≤128;

each dd is independently H, OH or a leaving group;

R ¹³⁰ is either a dendritic, branched or unbranched polyvalent group and is selected from optionally substituted alkylene, oligoalkylene or polyalkylene, and optionally substituted heteroalkylene, oligoheteroalkylene or polyheteroalkylene, and optionally substituted arylene, oligoarylene or polyarylene, and optionally substituted heteroareroarylene, and optionally substituted cycloalkylene, oligocycloalkylene or polycycloalkylene, and optionally substituted goethe rocycloalkylene, oligheterocycloalkylene or polyheterocycloalkylene, and - (CH ₂ CH ₂ O) _v -, -alkylene- (CH ₂ CH ₂ O) _v -, - (CH ₂ CH ₂ O) _v -alkylene-, -alkylene- (CH ₂ CH ₂ O) _v -alkylene-, -heteroalkylene- (CH ₂ CH ₂ O) _v -, - (CH ₂ CH ₂ O) _v -heteroalkylene-, -heteroalkylene- (CH ₂ CH ₂ O) _v -alkylene-, -heteroalkylene- (CH ₂ CH ₂ O) _v -heteroalkylene-, -alkylene- (CH ₂ CH ₂ O) _v -heteroalkylene-, X ¹⁴ (CH ₂ CH ₂ O) _gg CH ₂ CH ₂ X ¹⁴ , dendritic structure and an oligopeptide or any combination of two or more of the above compounds;

R¹³¹ and R¹³² independently selected from H, C_1-8 alkyl and C_1-8 heteroalkyl;

v is selected from 1 (inclusive) to 1000 (inclusive).

In another embodiment, L is selected from

,

,

where rr, rr 'and rr'', each independently, has values ranging from 0 to 8, each of X ⁴⁰ and X ^{41 is} independently selected from O, S and NR ¹³⁵ , where R ^{135 is} selected from H and C _{1- 3} alkyl, and each of uu, uu 'and uu''is independently selected from 0 and 1.

In another embodiment, L is selected from

In yet another embodiment, L contains a group X ¹⁴ (CH ₂ CH ₂ O) _gg CH ₂ CH ₂ X ¹⁴ , which, for example, may be

,

,

where gg 'is selected from 3 to 1000. In other embodiments, gg' is selected from 3 to 500 or 100 or 50 or 10. In other embodiments, gg 'is selected from 3 or 4 or 5.

In another embodiment, L is selected from

,

,

where X ⁷⁰ , X ⁷¹ , X ⁷² and X ^{73 are} independently selected from O, S and NR ⁸² , d is selected from 0 to 8, e is 0 or 1, gg "and gg * are independently selected from values from 1 to 1000, gg 'is selected from values from 3 to 1000, and R ⁸¹ and R ^{82 are} independently selected from H and optionally substituted C _1-3 alkyl.

The bond between L and V ¹ or Y , for example, may be an amide, carbonate or carbamate bond. Alternatively, when V ¹ is a peptide in which the N-terminal amino acid is an amino acid facial expression that carries an α-azido group instead of an α-amino group, the bond between L and V ¹ may be a triazole group formed through the interaction of an acetylene group, which is part L, and the α-azido group in V ¹ .

Reactive group RM and linking group L ²

The reactive RM group in the compound of formula (IV) is bound to the linking group L and is capable of interacting with a suitable functional group in the reaction partner.

In one of the embodiments of the present invention, the reactive group RM is designed to interact with a functional group in group V ² , which leads to the formation of the compounds of formula ( III ). In this reaction, the RM group is converted to the L ² group. In another embodiment, the reactive group RM is designed to react with a complementary group in situ , for example, in vivo , for example, with serum albumin, to produce a compound, which may or may not be a compound of formula ( III ).

In one aspect of the present invention, the reactive group RM contains an electrophilic group that interacts with a nucleophilic group in the reaction partner, for example, V ² , such as a thiol group, an amino group or a hydroxy group.

In another aspect of the present invention, the reactive group RM contains a nucleophilic group that interacts with an electrophilic group in a reaction partner, for example, V ² such as an aldehyde group.

In another aspect of the invention, the reactive group RM contains a fragment of a cycloaddition partner, for example, alkene, diene, 1,3-dipole or 1,3-dipolarophile, which interacts with a suitable fragment of a complementary cycloaddition partner in a reaction partner, for example, V ² , for example, diene alkene, 1,3-dipolarophil or 1,3-dipole.

In another aspect of the invention, the reactive group RM contains a group that may be linked to a suitable complementary group in the reaction partner, for example, V ² , under conditions of metal catalysis, biocatalysis or enzymatic catalysis, for example, under conditions of palladium catalysis.

In one aspect of the invention, the reactive group RM is, without limitation,

,

,

Where

X ³⁵ selected from halogen, hydroxy, OC (O) R^dd and OC (O) OR^dd, or C (O) -X ³⁵ is an activated ester,X ³⁶ selected from halide, mesyloxy, triflyloxy and tosyloxy, and R^dd selected from optionally substituted C_1-10 alkyl, C_1-10 heteroalkyl, C_3-10 cycloalkyl, C_1-10 heterocycloalkyl, C_5-10 aryl and c_1-10 heteroaryl.

In one embodiment, the RM group is selected from

which makes it capable of interacting with a thiol group in the reaction partner, for example, group V ² .

In another embodiment, the RM group is

which makes it capable of interacting with a thiol group in the reaction partner, for example, group V ² .

In another embodiment, the RM group is selected from

which makes it capable of interacting with an amino group, for example, a primary or secondary amino group, in a reaction partner, for example, a group V ² .

In another embodiment, the RM group is selected from

which makes it able to interact with the aldehyde group in the reaction partner, for example, group V ² .

When the reactive groupRM interacts withV ²linking groupL ² in the compound of the formula (III) represents the remainderRM. Then this group links the groupV ² fromL. The group that remains may be a bond, denoting thatL ² absent. However usuallyL ² represents a linking group. When the compound of the formula (III) is formed differently than by a compound of the formula(Iv),L ² does not constitute a remainderRM, but may represent a similar or similar group, and, in addition, be selected from, for example, optionally substituted C_1-10alkylene, C_1-10 heteroalkylene, C_3-10 cycloalkylene, C_1-10 heterocycloalkylene, C_5-10 arilene and C_1-10 heteroarylene. GroupL ² may optionally contain a groupX ^fourteen(CH₂CH₂O)_ggCH₂CH₂ X ^fourteen.

In one embodiment, the L ² group is absent.

In another embodiment, the group L ² represents, without limitation,

.

.

In an additional embodiment, the group L ² represents

.

.

Group V ²

GroupV ² represents functional group, which means adding additional functionality to the compound of the invention.

In one embodiment, V ² is a guide group. In another embodiment, the V ² group is a group that improves the pharmacological properties of the compounds of the invention. In yet another embodiment, the V ² group is a group that causes the accumulation of a compound of the invention at a target site. In yet another embodiment, the V ² group is a group that improves the aqueous solubility of a compound of the invention. In yet another embodiment, the V ² group is a group that increases the hydrophobicity of a compound of the invention. In yet another embodiment, the V ² group is a group that reduces the extravasation of a compound of the invention. In yet another embodiment, the V ² group is a group that reduces the release of a compound of the invention. In yet another embodiment, the V ² group is a group that reduces the immunogenicity of a compound of the invention. In yet another embodiment, the V ² group is a group that increases the circulation rate of a compound of the invention. In yet another embodiment, the V ² group is a group that enhances the ability of a compound of the invention to cross a biological barrier, for example, a membrane, cell wall or blood-brain barrier. In yet another embodiment, the V ² group is a group that improves the digestibility of the compound of the invention. In yet another embodiment, the V ² group is a group that promotes the digestibility of the compounds of the invention. In yet another embodiment, the V ² group is a group that promotes aggregation of a compound of the invention. In yet another embodiment, the V ² group is a group that reduces the aggregation of a compound of the invention. In yet another embodiment, the V ² group is a group that promotes the formation of micelles or liposomes with a compound of the invention. In yet another embodiment, the V ² group is a group that causes the formation of a complex of a compound of the invention with another molecule, for example, a biomolecule. In yet another embodiment, the V ² group is a polynucleotide fragment complexing with a complementary nucleotide sequence, for example, RNA or DNA. In yet another embodiment, the V ² group is a group that facilitates the bonding, association, interaction, or complexing with another group, for example, a (functionally) surface or solid support to a compound of the invention.

In another embodiment, V ² shows two or more different functions. Group V ² , for example, can be a targeting group and at the same time improve pharmacological properties, including water solubility.

In one aspect of the invention, group V ² includes within its scope any unit that binds or reacts with, or complexes with a receptor, receptor complex, antigen, or other group associated with a given population of target cells. V ² can be any molecule that binds, forms complexes, or interacts with a fragment of a cell population that seeks to be therapeutically or otherwise biologically transformed. Group V ² acts to deliver one or more Z groups to a particular population of a target cell with which V ² interacts or with which V ² is associated. Such V ² groups include, but are not limited to, aptamers, full-length antibodies and antibody fragments, and their derivatives, lectins, biological response modifiers, enzymes, vitamins, growth factors, steroids, nutrients, sugar groups, oligosaccharide groups, hormones, and any derivatives thereof, or any combination of any of these compounds. Upon binding, reactive binding or complexation, the compounds of the invention may or may not be absorbed. If assimilation, conversion and / or cleavage of V ¹ preferably occurs within the target cell.

Used non-immunoreactive protein, polypeptide or group V ² peptides include, but are not limited to, transferrin, epidermal growth factors ("EGF"), bombesin, gastrin and its derivatives, gastrin-releasing peptide derived from platelets of growth factor, IL-2, IL-6 transforming growth factors ("TGF"), such as TGF-α and TGF-β, tumor growth factors, growth factor from vaccinia virus ("VGF"), insulin and insulin-like growth factors I and II, lectins and apoprotein from low density lipoprotein.

The V ² polyclonal antibody groups used are heterogeneous populations of antibody molecules. Various methods well known in the art can be used to produce polyclonal antibodies to an antigen of interest.

The monoclonal antibody groups V ² used are homogeneous populations of antibodies to a particular antigen (e.g., cancer cell antigen). A monoclonal antibody (mAb) to an antigen of interest can be obtained using any method known in the art for producing monoclonal antibody molecules.

Useful V ² monoclonal antibody groups include, but are not limited to, human monoclonal antibodies, humanized monoclonal antibodies, or human-mouse chimeric monoclonal antibodies (or other species). Monoclonal antibodies can be obtained by any of numerous methods known in the art.

Group V ² may also be a bispecific antibody. Methods for producing bispecific antibodies are well known in the art.

Group V ² may be a functionally active group, derivative or analog of an antibody that immunospecifically binds to an antigen in a target cell, for example, a cancer cell antigen. In this sense, “functionally active” means that a group, derivative or analogue is capable of activating anti-anti-idiopathic antibodies that recognize the same antigen that recognizes the antibody from which the fragment, derivative or analogue is derived.

Other useful V ² groups contain antibody groups, including, but not limited to, F (ab ') ₂ fragments that contain a variable region, a light chain constant region, and a heavy chain CH1 domain that can be obtained by pepsin digestion of an antibody molecule, and Fab fragments, which can be formed by the reduction of disulfide bridges of F (ab ') ₂ fragments. Other useful V ² groups are antibody heavy and light chain dimers, or any minimal fragment thereof, such as Fvs or single chain antibody (SCA), domain of an antibody, anticalina, affinity, nanobody and any other molecules having similar, similar or comparable specificity as a parent antibody.

Additionally, recombinant antibodies, such as chimeric and humanized monoclonal antibodies containing both human and non-human parts, which can be obtained using standard recombinant DNA techniques, are the V ² fragments used. A chimeric antibody is a molecule in which different parts are obtained from animals of various species, such as those having a variable region derived from a murine monoclonal and human constant region of an immunoglobulin. Humanized antibodies are antibody molecules of non-human species having one or more hypervariable regions (CDR) of non-human species and a frame region of a human immunoglobulin molecule.

Fully human antibodies are particularly desirable as V ² groups. Such antibodies can, for example, be obtained using transgenic mice that are unable to express endogenous immunoglobulin heavy and light chain genes, but which can express human heavy and light chain genes.

In other embodiments, the V ² group is an antibody fusion protein or a functionally active fragment or derivative thereof, for example, one in which the antibody is fused via a covalent bond (eg, a peptide bond) or at the N-terminus or C-terminus with an amino acid sequence another protein (or part thereof, preferably at least 10, 20 or 50 amino acid parts of a protein) that is not an antibody. Preferably, the antibody or fragment thereof is covalently linked to another protein at the N-terminus of the constant domain.

Group V ² antibodies include analogs and derivatives that are converted, i.e. by covalent attachment of any type of molecule, provided that such covalent attachment allows the antibody to retain its antigen-binding immunospecificity. For example, but not by way of limitation, derivatives and analogs of antibodies include those that have been further transformed, for example, by glycosylation, acetylation, covalent attachment of polyethylene glycol polymer chains, disulfide reduction, phosphylation, amidation, derivatization using known protective or blocking groups, proteolytic cleavage binding to another protein, etc. Additionally, the analog or derivative may contain one or more non-natural amino acids.

Group V ² antibodies include antibodies having modifications (e.g., substitutions (e.g., cysteine to serine or serine to cysteine), deletions or additions), for example, in amino acid residues that interact with Fc receptors. In particular, they include antibodies having modifications in amino acid residues identified as being included in the interaction between the Fc domain and the FcRn receptor. Modifications may also be introduced to be able to couple the antibody to linker-agent conjugates at specific positions on the antibody.

In a specific embodiment, an immunospecific antibody to a cancer or tumor antigen is used as a groupV ² in accordance with the compounds, compositions and methods of the invention.

Immunospecific antibodies to a cancer antigen cell can be obtained commercially or obtained by any method known to one skilled in the art, such as chemical synthesis or recombinant expression methods. Nucleotide sequences encoding immunospecific antibodies to a cancer antigen cell can be obtained, for example, from a GenBank database or a similar database, from a commercial or other source, from literature, or by a conventional cloning and sequencing method.

Examples of antibodies available for the treatment of a malignant tumor that can be used to introduce into the conjugates of the present invention include, but are not limited to, HERCEPTIN (trastuzumab), which is humanized with anti-HER2 monoclonal antibody for the treatment of patients with metastatic breast cancer; RITUKSAN (rituximab), which is a chimeric anti-CD20 monoclonal antibody for the treatment of patients with non-Hodgkin's lymphoma; OvaRex (oregovomab), which is a murine antibody for the treatment of ovarian cancer; Panorex (edrecolomab), which is a murine IgG _2a antibody for the treatment of colorectal cancer; IMC-BEC2 (mitumomab), which is a murine IgG antibody for the treatment of lung cancer; IMC-C225 (Erbitux), which is a chimeric IgG antibody for the treatment of head and neck cancer; Vitaxin, which is a humanized antibody for the treatment of sarcoma; Campas I / H (alemtuzumab), which is a humanized IgG ₁ antibody for the treatment of chronic lymphocytic leukemia (CLL); SGN-70, which is a humanized anti-CD70 antibody for the treatment of hematologic malignancies; Smart MI95, which is a humanized IgG antibody for the treatment of acute myeloid leukemia (AML); J591, which is a murine antibody against a prostatic specific membrane antigen; LymphoCide (epratuzumab), which is a humanized IgG antibody for the treatment of non-Hodgkin lymphoma; SGN-33, which is a humanized anti-CD33 antibody for the treatment of acute myeloid leukemia; Smart ID 10, which is a humanized antibody for the treatment of non-Hodgkin lymphoma; Oncolim, which is a murine antibody for the treatment of non-Hodgkin lymphoma; Allomun, which is a humanized anti-CD2 mAb for the treatment of Hodgkin's disease or non-Hodgkin's lymphoma; Avastin (bevacizumab), which is a humanized anti-VEGF antibody for the treatment of lung cancer and colorectal cancer; SGN-40, which is a humanized anti-CD40 antibody for the treatment of multiple myeloma; SGN-30, which is a chimeric anti-CD30 antibody for the treatment of Hodgkin's disease; CEAcide, which is a humanized anti-CEA antibody for the treatment of colorectal cancer; IMC-1C11, which is an anti-KDR chimeric antibody for the treatment of colorectal cancer, malignant tumors of the lungs and melanoma; and Cetuximab, which is an anti-EGFR chimeric antibody for treating a positive malignant tumor with expressions of epidermal growth factor.

Other antibodies used to treat a cancer include, but are not limited to, antibodies against the following antigens: CA125, CA9, CA6, CA15-3, CA19-9, L6, Lewis Y, Lewis X, alpha fetoprotein, CA 242, placental alkaline phosphatase, prostatic specific antigen (PSA), prostatic specific membrane antigen (PSMA), prostatic acid phosphatase, epidermal growth factor receptors, interleukin receptors, insulin-like growth factor receptors, CanAg, DAF, PEM, IRTA-2, IRTA-4, AFP , HER2, EGFR, VEGFR1, VEGFR2, MAGE-1, LUCA1, LUCA2, MAGE-2, MAGE-3, MAGE-4, ED-B, MADCAM, MCP-1, TAT226, VLA-4, C3B, anti-transferrin receptor, Syndecan-1, ROBO4, STEAP-1, CMET, Eph tyrosine kinase receptor, PSCA, CLL-1, TNF-α, FAP-α, IFN-α, EphA2, EphB2, EphB4 , EGFL-7, DLL-4, RS7, 4-1BB, TENB2, FLT3, p97, FGF19, FGFR2, glypican-3, P53, RON, GFR-α3, FDF03, TSLPR, MUC1-KLH, MUC18, B7H4, PTK7 , RG-1, MUC16, CSAP, PSMA, 5T4, EpCAM, IGF1R, CCR2, CCR5, CTLA4, CLCA-1, DR5, CEA, CXCR-4, GD2, gp100, GD3 ganglioside, L243, HMGB1, GPC-3, MART1, IL-2 receptor, CD2, CD3, CD4, CD20, CD43, CD44, CD30, CD55, CD151, CD154, CD19, CD23, CD79, CD52, CD25, CD46, CD56, CD59, CD7, CD138, CD74, CD133 , CD80, CD63, CD64, CD66, CD140b, CD32, CD33, CD37, CD22, Apo-2, ERBB4, HLA-DR, HLA-DR10, human chorionic gonadotropin, CD38, CD40, CD70, mucin, P21, MPG and oncoproduct the Neu gene. Various other internalizing or non-internalizing antibodies that bind to tumor-specific antigens can be used in the present invention as a V ² fragment, some of which were examined ¹⁴ .

In some embodiments, the antibody is an antinuclear antibody or antibody that can bind to a receptor or receptor complex expressed in a target cell. The receptor or receptor complex may comprise a member of the immunoglobulin gene superfamily, integrin, a chemokine receptor, a member of the TNF receptor superfamily, a cytokine receptor, a histocompatibility complex protein, a control complex protein, or a lectin.

In another specific embodiment, an immunospecific antibody to an antigen associated with an autoimmune disease is used asV ² fragment in accordance with the compounds, compositions and methods of the invention. In another specific embodiment, an immunospecific antibody to a viral or microbial antigen is used asV ² fragment in accordance with the compounds, compositions and methods of the invention. As used herein, the term “viral antigen” includes, but is not limited to, any viral peptide or polypeptide protein capable of eliciting an immune response. As used herein, the term “microbial antigen” includes, but is not limited to, any microbial peptide, polypeptide, protein, saccharide, polysaccharide or lipid that is capable of eliciting an immune response.

New antibodies are continuously being discovered and developed, and the present invention relates to these new antibodies, which may also be included in the scope of the present invention.

V ² can interact with the reactive group RM through, for example, a heteroatom in V ² . Hetero atoms that may be present in V ² include, but are not limited to, sulfur (in one embodiment from a sulfhydryl group), oxygen (in one embodiment from a carboxyl or hydroxyl group), and nitrogen (in one embodiment from primary or secondary amino group). V ² can also interact via, for example, a carbon atom (in one embodiment from a carbonyl group). These atoms can be present in V ² in the natural state of V ² , for example, a natural antibody, or can be introduced into V ² through a (chemical) conversion.

Free sulfhydryl groups can be formed in the antibody or antibody fragment by reducing the antibody (fragment) with a reducing agent such as dithiothreitol (DTT) or Tris (2-carboxyethyl) phosphine (TCEP). Thus, transformed antibodies can be prepared so that they can have from 1 to about 20 sulfhydryl groups, but usually from about 1 and about 9 sulfhydryl groups.

Alternatively, V ² may have one or more carbohydrate groups which can be chemically converted to contain one or more sulfhydryl groups. As another alternative, sulfhydryl groups can be formed by reacting amino groups, for example, from lysine fragments, in V ² with 2-iminothiolane (Trot's reagent), N-succinimidyl S-acetylthioacetate (SATA) or other sulfhydryl-forming reagent.

In one embodiment, the V ² fragment is a receptor binding group.

In another embodiment, the V ² fragment is an antibody or antibody fragment or derivative thereof.

In another embodiment, the V ² fragment is a monoclonal antibody or fragment or derivative thereof.

In one embodiment, V ² has one or more sulfhydryl groups, and V ² interacts with one or more RM groups of one or more compounds of formula (IV) through one or more of these sulfur atoms of sulfhydryl groups to form a compound of formula ( III ), in which thus includes one or more compounds of formula (IV) .

In yet another embodiment, V ² contains one or more disulfide bonds that can be chemically reduced to sulfhydryl groups (two for each disulfide bond), which can then react with one or more reactive RM groups to form a compound of formula ( III ).

In another embodiment, V ² contains from about 1 to about 3 sulfhydryl groups that can react with one or more reactive RM groups to form a compound of formula (III) .

In another embodiment, V ² contains from about 3 to about 5 sulfhydryl groups that can react with one or more reactive RM groups to form a compound of formula ( III ).

In another embodiment, V ² contains from about 7 to about 9 sulfhydryl groups that can react with one or more reactive RM groups to form a compound of formula ( III ).

In another embodiment, V ² may have one or more carbohydrate groups that can be chemically converted so as to have one or more sulfhydryl groups. V ² interacts with RM fragments through one or more sulfur atoms of these sulfhydryl groups to form a compound of formula ( III ).

In another embodiment, V ² may have one or more lysine groups that can be chemically converted so as to have one or more sulfhydryl groups that can react with one or more reactive RM moieties to form a compound of formula ( III ).

Reactive fragments that can interact with a sulfhydryl group include, but are not limited to, carbamoyl halide, acyl halide, α-haloacetamide, halogen methyl ketone, vinyl sulfone, maleimide and 2-disulfanyl pyridine.

In yet another embodiment, V ² may have one or more carbohydrate groups that can be oxidized to produce one or more aldehyde groups. Then, the corresponding aldehyde (s) (s) can (gut) react with one or more reactive RM groups to form a compound of formula ( III ). Reactive groups that can interact with the aldehyde group in V ² include, but are not limited to, hydrazine, hydrazide, amine, and hydroxylamine.

In yet another embodiment, V ² may have one or more amino groups, for example, of lysine residues, which can react with one or more reactive RM groups to form a compound of formula ( III ). Reactive fragments that can interact with the amino group include, but are not limited to, carbamoyl halide, α-haloacetamide, acyl halide, aldehyde, sulfonyl chloride, alkyl halide, alkyl sulfonate, isocyanate and isothiocyanate.

The conjugate of formula ( III ) may exist as a mixture, where each component of the mixture has a different q value. For example, a compound may exist as a mixture of two separate compounds, one compound where q is 2 and another compound where q is 3. As another example, the compound may exist as a mixture of 5 separate compounds in which q is 1, 2, 3, 4 and 5, respectively. As another example, a compound may exist as a mixture of more than 5 separate compounds. Such mixtures could also be “contaminated” with unconjugated V ² . When analyzing the compounds of formula ( III ), it should be taken into account that q can be equal to (rounded) the average number of units L ² - L (- ( V ¹ - Y )) _p ( Z ) _{z / q} per group V ² . In addition, for a given q, the compound can exist as a mixture of (structural) isomers, since q groups L ² - L (- ( V ¹ - Y )) _p ( Z ) _{z / q} can be associated with different (series) functional groups on v ² . It should be noted that a certain number of Z groups in each link is only equal to z / q if all links are the same and / or contain the same number of Z groups.

In one embodiment, the groupV ² connected withL ² through the sulfur atom toV ².

In another embodiment, the groupV ² connected withL ² through a sulfur atom and q values vary from about 1 to about 20.

In another embodiment, the groupV ² connected withL ² through a sulfur atom and q values vary from about 1 to about 9.

In another embodiment, the groupV ² connected withL ² through a sulfur atom and q values vary from about 1 to about 3.

In another embodiment, the groupV ² connected withL ² through a sulfur atom and q is approximately 2.

In another embodiment, the groupV ² connected withL ² through a sulfur atom and q values vary from about 3 to about 5.

In another embodiment, the groupV ² connected withL ² through a sulfur atom and q is approximately 4.

In another embodiment, the groupV ² connected withL ² through a sulfur atom and q values vary from about 7 to about 9.

In another embodiment, the groupV ² connected withL ² through a sulfur atom and q is approximately 8.

In one embodiment, the compound of formula ( III ) exists as a mixture of the individual compounds.

In one embodiment, the compound of formula ( III ) exists as a mixture of the individual compounds, where q for the three compounds is 1, 2, and 3, respectively.

In one embodiment, the compound of formula ( III ) exists as a mixture of the individual compounds, where q for the three compounds is 3, 4, and 5, respectively.

In one embodiment, the compound of formula ( III ) exists as a mixture of the individual compounds, where q for the three compounds is 5, 6, and 7, respectively.

In one embodiment, the compound of formula ( III ) exists as a mixture of the individual compounds, where q for the three compounds is 7, 8, and 9, respectively.

In another embodiment, the groupV ² connected withL ² across nitrogen atom onV ².

In yet another embodiment, the groupV ² connected withL ² across carbon atom onV ².

In another aspect of the present invention, a groupV ² includes any unit that causes the accumulation of the compounds of the invention at or near the target site using a mechanism different from binding or reactive association or complexation with a receptor, antigen or other receptive group associated with this target site, for example, a population of cells targets. One way to achieve this is, for example, the use of a large macromolecule, such as a groupV ², which achieves its goal - solid tumor tissue - due to the effect of increased permeability and retention (EPR). Ringsdorf Announces Use of Targeting Polymers for Tumor Antitumor Agents^fifteen. Through this effect, EPR macromolecules passively accumulate in solid tumors as a result of a pathological disorder of the vascular system of the angiogenic tumor with its intermittent endothelium, leading to increased permeability for large macromolecules, and the absence of effective lymphatic drainage in the tumor.

Group V ² , for example, can be a branched or unbranched polymer, such as, for example, poly [ N - (2-hydroxypropyl) methacrylamide] (HPMA), hydroxyethyl starch (HES), poly (2-hydroxyethyl methacrylate) (HEMA), polyglutamic acid or poly-L-glutamic acid (PG), carboxymethyldextran (CMDex), polyacetal, chitosan, polypeptide, oligoethylene glycol or polyethylene glycol (PEG) or a copolymer such as HPMA copolymer, HPMA methacrylic acid copolymer, HEM copolymer CMDex copolymer, β-cyclodextrin copolymer, PEG copolymer if poly (lactic-co-glycolic) acid ^16. As used herein, both a polymer and a copolymer are referred to as a polymer.

The polymer may be coupled to L ² via any suitable functional group that may be located at one or both ends of the polymer, implying that in the conjugate q has values in the range of 1 to 2, or, alternatively, the functional groups may (also) be located on groups suspended on the polymer such that L ² (also) is bonded to the polymer via these side groups with q typically in the range of 1 to about 1000. Optionally, the polymer may also contain an additional targeting group that can bind bite or react with or complex with a receptor fragment, for example, an antibody or antibody derivative, linked to a polymer or via a side group or an end group, so as to achieve improved targeting to the target site.

Alternatively, the V ² fragment may be a dendrimer or a protein or protein fragment, for example, serum albumin, which does not have targeting properties. apart from its ability to accumulate on the target site due to its size or molecular weight.

In one embodiment, the fragment V ² contains a polymer.

In another embodiment, the V ² fragment is a polymer.

In another embodiment, the V ² fragment is a polymer and the q value is in the range of 1 to about 1000.

In other embodiments, the V ² fragment is a polymer and the q value ranges from 1 to about 500 or 400 or 300 or 200 or 100 or less than 100.

In another embodiment, the V ² fragment is a polymer and q has a value in the range of 1 to 2.

In another embodiment, the fragment V ² is a polymer and q is 1.

In a specific embodiment, the V ² fragment is oligoethylene glycol or polyethylene glycol or a derivative thereof.

In another embodiment, the V ² fragment is a dendrimer, protein, or protein fragment.

In another embodiment, V ^{2 is} absent.

In another embodiment, the V ² fragment is a group that is capable of transporting a conjugate through a biological barrier, for example, a cell membrane, with or without pre-binding, by joining or complexing with a receptor or receptor complex. In one embodiment, the V ² fragment is a Tat peptide or derivative, a fragment or its analogue, or a group that has similar transmembrane delivery properties. In another embodiment, the V ² fragment is a protein or protein fragment, an antibody or antibody fragment, a receptor-binding fragment or a fragment of a peptide vector, or a polymer or dendritic fragment, or any combination thereof, to which a Tat peptide or derivative, fragment or its analogue is attached , or a group that has similar transmembrane delivery properties.

Thus, in one aspect of the invention, group V ² is a targeting fragment and is selected from the group consisting of a protein or protein fragment, an antibody or antibody fragment, a receptor-binding fragment or fragment of a peptide vector, and a polymer or dendritic fragment and any combination thereof or derivative.

In another aspect of the invention, the V ² fragment is a fragment that improves the pharmacological properties of the conjugate of the invention. For example, group V ² can be selected so that the water solubility of the conjugate is (additionally) improved. This can be achieved by choosing V ² as the hydrophilic fragment. Alternatively, the V ² fragment can be used, for example, to increase the retention time of the compound in the bloodstream, to reduce extravanasia and / or excretion, reduce aggregation and / or reduce the immunogenicity of the compound. This can be achieved, for example, by choosing V ² , which will be or comprise polyethylene glycol or oligoethylene glycol or a derivative thereof. When the group V ² is a group that improves the pharmacological properties of the compounds of the invention, and V ¹ is a group that can be cleaved or converted non-specifically and V ^{1 '} and V ^2' fragments are not present, the compound serves only for improvement (pharmacological ) properties of one or more Z fragments.

In one embodiment, V ² is a group that improves pharmacological properties, and V ¹ is a group that can be cleaved or converted specifically.

In another embodiment, V ² is oligoethylene glycol or polyethylene glycol or a derivative thereof, and V ¹ is a group that can be cleaved or converted specifically.

In another embodiment, V ² is a group that improves pharmacological properties, and V ¹ is a group that can be cleaved or converted non-specifically.

In another embodiment, V ² is oligoethylene glycol or polyethylene glycol or a derivative thereof, and V ¹ is a group that can be cleaved or converted non-specifically.

In another embodiment, V ² is oligoethylene glycol or polyethylene glycol or a derivative thereof, and V ¹ is a group that can be cleaved by ubiquitous enzymes.

In another embodiment, V ² is oligoethylene glycol or polyethylene glycol or a derivative thereof, and V ¹ is a hydrolyzable group.

In another embodiment, V ² contains X ¹⁴ (CH ₂ CH ₂ O) _gg CH ₂ CH ₂ X ¹⁴ group.

In one aspect of the present invention, group V ² is represented by formula ( VI ):

where V ^{2 *} , L ^{2 *} , L * , V ^{1 *} , Y * , p *, q * and z * have the same meanings as defined for V ² , L ² , L , V ¹ , Y , p, q and z, respectively, as defined herein, and are independently selected, except that Y * is associated with L ² . It should be noted that z * is actually equal to q, assuming that all Y * are actually associated with L ² . When the compound of formula ( III ) contains a group V ² represented by formula ( VI ), one or more groups of L ^{2 are} thus linked to Y * .

The use of a V ² group of formula ( VI ) in a conjugate of formula ( III ) means that two conditionally split or conditionally convertible groups may lie between the functional group V ² and Z , and thus two separate cleavages / conversions may be necessary to release Z . The requirement that two different conditions be met - sequentially - before one or more Z are released, can have a beneficial effect on the properties of the conjugate. For example, this can increase targeting efficiency and therapeutic conjugate index. Two transformations / cleavages can occur at different extracellular / intracellular positions. A group to be removed by a second cleavage or as a result of a second transformation, for example, can be used to help transfer Z from the first extracellular or intracellular position (where the first cleavage occurred) to the second extracellular or intracellular position, or stabilize Z while it is located close to its target, or to (temporarily) increase the water solubility of Z. To increase targeting efficiency and / or therapeutic index, using this principle, the second transformation and / or splitting should occur only after the first transformation and / or splitting occurs. If a second conversion and / or splitting can also occur before the first conversion and / or splitting occurs, an improvement in targeting efficiency and / or an improvement in the therapeutic index by virtue of this principle seems unlikely.

Obviously, a group V ^{2 of} formula ( VI ) or a progroup containing such V ² can not only be used in conjugates of a compound of formula ( I ) or ( II ), but can be used in similar conjugates of other therapeutic agents, diagnostic fragments, etc. P.

A compound of formula ( III ) containing a group V ^{2 of} formula ( VI ) can be prepared from compounds of formula ( III ) containing a group V ^{2 of} formula ( VII ):

where RM * has the same meaning as defined for RM, and is independently selected.

Please note that in this document, whenever V ² , L ² , L , V ¹ , Y , RM , p, q or z are specified, a similar one can be applied to each V ^{2 *} , L ^{2 *} , L * , V ^{1 *} , Y * , RM * , p *, q * or z *, respectively, unless otherwise indicated in the context.

It should be noted that the functional group V ² may have several combined functional properties. For example, V ² may be a group that improves the pharmacological properties of the compounds of the present invention, and at the same time represent or contain a targeting group.

The conjugates of the present invention may contain one or more progroups. These progroups may be the same or different. The presence of two or more progroups may have a beneficial effect on conjugate properties. For example, this can increase water solubility and / or increase the efficiency of targeting the conjugate. In addition, if two progroups are present in the targeted conjugate and the progroup necessary for targeting is prematurely cleaved from Z , for example, in the bloodstream, the second progroup weakens the cytotoxicity of Z.

In one embodiment, when two or more progroups are present, said progroups are different from each other. Two or more different progroups can have different functions and can be removed under different conditions and at different extracellular / intracellular positions.

In one embodiment, one progroup associated with Z is present. In another embodiment, there is one progroup associated with Z through X ¹ . In another embodiment, two progroups associated with Z are present. In another embodiment, there are two progroups associated with Z , of which one is linked via X ¹ . In another embodiment, there are two progroups associated with Z , of which one is linked via X ¹ and the other with a DNA alkylating unit. In another embodiment, there are two progroups associated with Z , of which one is linked via X ¹ and the other to a DNA link. In another embodiment, there are two progroups associated with Z , of which one is linked to a DNA-binding unit and the other to a DNA-alkylating unit. In yet another embodiment, three progroups associated with Z are present. In yet another embodiment, there are three progroups associated with Z , of which one is linked via X ¹ .

In one aspect of the present invention, a compound of formula (III) contains at least 2 progroups. The first progroup contains at least a targeting group, and the second contains at least a groupX ^fourteen(CH₂CH₂O)_ggCH₂CH₂ X ^fourteen or 2 groupsX ^fourteenCH₂CH₂Och₂CH₂ X ^fourteen, and is presentV ^one' specified the same second progroup. Similarly, the compound of the formula(Iv) may contain at least 2 progroups. The first progroup contains at least a reactive groupRM2, and the second contains at least a groupX ^fourteen(CH₂CH₂O)_ggCH₂CH₂ X ^fourteen or 2 groupsX ^fourteenCH₂CH₂Och₂CH₂ X ^fourteenis presentV ^one' specified the same second progroup. These second progroups of compounds of formulas (III) and(Iv)for example can be represented

In one embodiment, said second progroup is selected from

where X ⁷⁰ , X ⁷¹ , X ⁷² and X ^{73 are} independently selected from O, S and NR ⁸² , d is selected from 0 to 8, e is 0 or 1, gg "and gg * are independently selected from 1-1000, gg 'is selected from 3-1000, and R ⁸¹ and R ^{82 are} independently selected from H and optionally substituted C _1-3 alkyl.

In another embodiment, said second progroup is selected from

In a further embodiment, said second progroup is selected from

where AS is

where f is 0, 1 or 2, g is 0 or 1, and PM is an amino acid or peptide linked at its N-terminus to L ' .

In further embodiments, said second progroup is selected from

where AS is

where f is 0, 1 or 2, g is 0 or 1, PM is selected from valylcytrulline, valyllisine, phenylalanyllysine, alanylphenylalanyllysine and D-alanylphenylalanyllysine bonded at its N-terminus to L ' , and gg' is selected from 3-1000 or 500 , or 100, or 50, or 10, or 5.

In one embodiment, a compound of formula ( III ) is represented by a compound of formula ( III-1 ) or ( III-2 ):

In another embodiment, a compound of formula ( III ) is represented by a compound of formula ( III-3a ) or ( III-4a ), wherein the DNA binding group is DB 1 :

,

,

where Y ' is bonded to an atom that is part of X ³ , X ³⁴ , X ⁴ , X ⁶ , X ⁷ , X ⁸ , X ⁹ , X ¹¹ or X ¹² .

In another embodiment, the compound of formula ( III ) is represented by the compound of formula ( III-3b ) or ( III-4b ), where the DNA binding group is DB2 :

,

,

where Y ' is bonded to an atom that is part of X ³ , X ³⁴ , X ⁴ , X ⁶ , X ⁷ , X ⁹ , X ¹¹ or X ¹² .

In another embodiment, a compound of formula ( III ) is represented by a compound of formula ( III-3c ) or ( III-4c ), where the DNA binding group is DB 3 :

,

,

where Y ' is bonded to an atom that is part of X ⁶ , X ⁷ , X ⁸ , X ⁹ , X ¹⁰ or X ¹¹ .

In another embodiment, a compound of formula ( III ) is represented by a compound of formula ( III-3d ) or ( III-4d ), wherein the DNA binding group is DB4 :

,

,

where Y ' is bonded to an atom that is part of X ⁶ , X ⁷ , X ⁸ , X ⁹ or X ¹¹ .

In another embodiment, a compound of formula ( III ) is represented by a compound of formula ( III-3e ) or ( III-4e ), where the DNA binding group is DB5 :

,

,

where Y ' is bonded to an atom that is part of R ^8b , R ^9b , X ³ , X ³⁴ , X ⁴ , X ⁷ or X ¹¹ .

In another embodiment, the compound of formula ( III ) is a compound of formula ( III-3f ) or ( III-4f ), where the DNA binding group is DB6 :

,

,

where Y ' is bonded to an atom that is part of X ³ , X ³⁴ , X ⁴ , X ^{6 *} , X ^{7 *} , X ⁷ , X ⁸ , X ^{8 *} , X ^{9 *} , X ^{10 *} or X ^{11 *} .

In another embodiment, the compound of formula ( III ) is a compound of formula ( III-3g) or ( III-4g ), where the DNA binding group is DB7 :

,

,

where Y ' is bonded to an atom that is part of X ³ , X ³⁴ , X ⁴ , X ^{6 *} , X ⁷ , X ^{7 *} , X ⁸ , X ^{8 *} , X ^{9 *} or X ^{11 *} .

In another embodiment, the compound of formula ( III ) is a compound of formula ( III-3h ) or ( III-4h ), where the DNA binding group is DB8 :

,

,

where Y ' is bonded to an atom that is part of X ³ , X ³⁴ , X ⁴ , X ⁷ or X ⁸ .

In another embodiment, the compound of formula ( III ) is a compound of formula ( III-3i ) or ( III-4i ), where the DNA binding group is DB9 :

,

,

where Y ' is bonded to an atom that is part of X ⁶ , X ⁷ , X ⁸ , X ⁹ or X ¹¹ .

The present invention further relates to compounds of formulas ( III-3j ) - ( III-3r ) and ( III-4j ) - ( III-4r ), which are similar to compounds of formulas ( III-3a ) - ( III-3i ) and ( III- 4a ) - ( III-4i ), respectively, except that the two progroups are reversed, and now Y is linked to an atom in the DNA-linking link, and Y ' is linked to X ¹ .

It should be noted that if in any of the compounds ( III-3a ) - ( III-3i ) and ( III-4a ) - ( III-4i ), Y ' is bonded to a ring atom that is part of ring A or ring B, rather than with an atom in the substituent R bonded to the ring atom, this actually means that such a substituent R is absent, if necessary to comply with the rules of valency. The same applies to Y in the compounds of formulas ( III-3j ) - ( III-3r ) and ( III-4j ) - ( III-4r ).

In another embodiment, a compound of formula ( III ) is represented by a compound of formula ( III-5a ) or ( III-6a ):

,

,

where Y ' is bonded to an atom that is part of R ⁵ , R ^5' , R ⁶ , R ^{6 '} , R ⁷ , R ^7' , R ¹⁴ , R ^{14 '} , X ² or to any of the atoms bearing these R.

In an additional embodiment, the compound of formula ( III ) is represented by compounds of formulas ( III-5b ) and ( III-6b ), which are similar to compounds ( III-5a ) and ( III-6a ), respectively, except that the two progroups are interchanged , and now Y is bonded to the atom in the DNA alkylating unit, and Y ' is bonded to X ¹ .

When Y ' in the compounds of formulas ( III-5a ) and ( III-6a ) is bonded to a ring atom, and not to an atom in the substituent R bonded to said ring atom, this actually means that such a substituent R is absent, if necessary for compliance with valency rules. The same applies to Y in the compounds of formulas ( III-5b ) and ( III-6b ).

In one embodiment, the implementation of the group V ^{2 '} (- L ^2' - L ' (- ( V ^1' - Y ' )) _p' ) _{q '} ( Z' ) _z'-1 in any of the compounds of formulas ( III-3a ) - ( III-3r ), ( III-4a ) - ( III-4r ), ( III-5a ), ( III-5b ), ( III-6a ) and ( III-6b ) are represented

In another embodiment, the group V ^{2 '} (- L ^2' - L ' (- ( V ^1' - Y ' )) _p' ) _{q '} ( Z' ) _z'-1 in any of the compounds of formulas ( III-3a ) - ( III-3r ), ( III-4a ) - ( III-4r ), ( III-5a ), ( III-5b ), ( III-6a ) and ( III-6b ) represented

In a further embodiment, the group V ^{2 '} (- L ^2' - L ' (- ( V ^1' - Y ' )) _p' ) _{q '} ( Z' ) _z'-1 in any of the compounds of formulas ( III-3a ) - ( III-3r ), ( III-4a ) - ( III-4r ), ( III-5a ), ( III-5b ), ( III-6a ) and ( III-6b ) selected from

where X ⁷⁰ , X ⁷¹ , X ⁷² and X ^{73 are} independently selected from O, S and NR ⁸² , d is selected from 0-8, e is 0 or 1, gg "and gg * are independently selected from 1-1000, gg 'is selected from 3-1000, and R ⁸¹ and R ^{82 are} independently selected from H and optionally substituted C _1-3 alkyl.

In one embodiment, p is an integer from 1 (inclusive) to 128 (inclusive). In another embodiment, q is an integer from 1 (inclusive) to 1000 (inclusive). In other embodiments, p is an integer from 1 (inclusive) to 64 (inclusive) or 32 (inclusive), or 16 (inclusive), or 8 (inclusive), or 4 (inclusive), or 2 (inclusive) , or p is 1. In other embodiments, q is an integer from 1 (inclusive) to 500 (inclusive) or 400 (inclusive), or 300 (inclusive), or 200 (inclusive), or 100 (inclusive) , or 16 (inclusive), or 8 (inclusive), or 6 (inclusive), or 4 (inclusive), or 2 (inclusive), or q is 1.

In one embodiment, if more than 1 progroup is associated with the first Z group and in one of the progroups there is more than one attachment site for Z groups, then the other of the indicated progroups associated with the specified first Z group each contains a separate attachment site for the group Z

In one embodiment, the compound of formula ( III ) is represented by the structure

.

.

In one embodiment, p in the compound of formula ( IIIa ) is 1.

In another embodiment, in the compound of formula ( IIIa ), p is 1 and z is q, which reduces formula ( IIIa ) to:

In another embodiment, the compound of formula ( IIIa ) is represented by the structure

or an isomer or a mixture of isomers, where R ⁵ , R ⁶ , R ⁷ , R ¹⁴ and DB are as defined above, V ^{1 is} selected from valicitrulline, vallylisine, phenylalanyllysine, alanylphenylalanyllysine and D-alanylphenylalanyllysine, f is 1 or 2, L is selected of

,

,

q has values ranging from 1 to 20, rr, rr 'and rr''each, independently, has values ranging from 0 to 8, each of X ⁴⁰ and X ^{41 is} independently selected from O, S and NR ¹³⁵ , where R ^{135 is} selected from H and C _1-3 alkyl, each of uu, uu 'and uu''is independently selected from 0 and 1, and Ab is an antibody or fragment or derivative thereof.

In another embodiment, the compound of formula ( IIIa ) is provided

or an isomer or a mixture of isomers, where R ⁵ , R ⁶ , R ⁷ , R ¹⁴ and DB are as defined above, V ¹ and V ^{1 ′ are} independently selected from valicitrulline, valillizine, phenylalanyllysine, alanylphenylalanyllysine and D-alanylphenylalanyllysine, f is 1 or 2, f 'is 0, 1 or 2, g' is 0 or 1, a dimethylaminoethylene group - or a p- aminobenzyloxycarbonyl group, if g 'is 0, or a group V ^1' , if f 'is also 0 - is bonded to an atom in DB , L is selected from

,

,

q has values ranging from 1 to 20, rr, rr 'and rr'', each independently has values ranging from 0 to 8, each of X ⁴⁰ and X ^{41 is} independently selected from O, S and NR ¹³⁵ , where R ^{135 is} selected from H and C _1-3 alkyl, each of uu, uu 'and uu''is independently selected from 0 and 1, Ab is an antibody or fragment or derivative thereof, and L' is selected from

,

,

where gg 'is selected from 3 to 1000.

In another embodiment, the compound of formula ( IIIa ) is provided

or an isomer or a mixture of isomers, where R ⁵ , R ⁶ , R ⁷ , R ¹⁴ and DB are as defined above, V ¹ and V ^{1 ′ are} independently selected from valicitrulline, valillizine, phenylalanyllysine, alanylphenylalanyllysine and D-alanylphenylalanyllysine, f is 0 , 1 or 2, f 'is 1 or 2, g is 0 or 1, a dimethylaminoethylene group is either a p- aminobenzyloxycarbonyl group, if g is 0, or a V ¹ group, if f is also 0, is bound to an atom in DB , L selected from

q has values ranging from 1 to 20, rr, rr 'and rr''each, independently, has values ranging from 0 to 8, each of X ⁴⁰ and X ^{41 is} independently selected from O, S and NR ¹³⁵ , where R ^{135 is} selected from H and C _1-3 alkyl, each of uu, uu 'and uu''is independently selected from 0 and 1, Ab is an antibody or fragment or derivative thereof, and L' is selected from

,

,

where gg 'is selected from 3 to 1000.

In another embodiment, the compound of formula ( III ) is provided

In one embodiment, p * in the compound of formula ( IIIa * ) is 1.

In another embodiment, in the compound of formula ( IIIa * ), p * is 1 and z * is q *.

In another embodiment, in the compound of formula ( IIIa * ), p * is 1, and z * and also z are q *, which reduces the formula ( IIIa * ) to:

In another embodiment, the compound of formula ( III ) is provided

In one embodiment, p in the compound of formula ( IIIb ) is 1.

In another embodiment, p in the compound of formula ( IIIb ) is 1, and z is q, which reduces formula ( IIIb ) to:

In another embodiment, the compound of formula ( III ) is provided

.

.

In one embodiment, p * in the compound of formula ( IIIb * ) is 1.

In another embodiment, in the compound of formula ( IIIb * ), p * is 1 and z * is q *.

In yet another embodiment, in the compound of formula ( IIIb * ), p * is 1 and z * and also z are q *, which reduces the formula ( IIIb * ) to:

In another embodimentV ^one in the compound of the formula (IIIb *) is an enzyme-cleavable substrate. In a further embodimentV ^one can be cleaved by the intracellular enzyme. In another embodimentV ^one represents optionally substitutedN,Na dialkylaminocarbonyl group, where the two alkyl groups may be the same or different and optionally be linked to each other to form an optionally substituted heterocycle. In yet another embodimentV ^one is piperazinocarbonyl. Such a groupV ^one may be enzymatically cleaved, for example, by carboxyl esterase.

In another embodiment, the compound of formula ( IIIb * ) is represented

or an isomer or a mixture of isomers, where R ⁵ , R ⁶ , R ⁷ , R ¹⁴ and DB have the meanings indicated above, V ^{1 * is} selected from valicitrulline, vallylisine, phenylalanyllysine, alanylphenylalanyllysine and D-alanylphenylalanyllysine, f * is 1 or 2, L * selected from

q * has values ranging from 1 to 20, rr, rr 'and rr''each, independently, has values ranging from 0 to 8, each of X ⁴⁰ and X ^{41 is} independently selected from O, S and NR ¹³⁵ , where R ^{135 is} selected from H and C _1-3 alkyl, each of uu, uu 'and uu''is independently selected from 0 and 1, and Ab is an antibody or fragment or its derivative.

In another embodiment, the compound of formula ( III ) is provided

In yet another embodiment, the compound of formula ( III ) is provided

.

.

In one embodiment, the compound of formula ( IIId ) is

or an isomer or a mixture of isomers, where R ⁵ , R ⁶ , R ⁷ , R ¹⁴ and DB are as defined above, f 'is 0, 1 or 2, g' is 0 or 1, V ^{1 'is} selected from valicitrulline, vallysine , phenylalanyllysine, alanylphenylalanyllysine and D-alanylphenylalanyllysine or absent, dimethylaminoethylene group - or p- aminobenzyloxycarbonyl group, if g 'is 0, or V ^1' group if f 'is also 0, or L' group if V ^{1 '} group is also absent - bound to an atom in DB , L ' selected from

q 'has values ranging from 1 to 20, rr, rr' and rr '' each independently has values ranging from 0 to 8, each of X ⁴⁰ and X ^{41 is} independently selected from O, S and NR ¹³⁵ , where R ^{135 is} selected from H and C _1-3 alkyl, each of uu, uu 'and uu''is independently selected from 0 and 1, Ab is an antibody or fragment or derivative thereof, and V ^{1 is} selected from mono-, di- or oligosaccharide or its derivative and

where R ¹⁴¹ , R ¹⁴² and R ^{143 are} independently selected from H and optionally substituted C _1-8 alkyl, C _1-8 heteroalkyl, C _3-8 cycloalkyl, C _1-8 heterocycloalkyl, C _5-8 aryl, or C _1-8 heteroaryl.

In another embodiment, the compound of formula ( IIId ) is

or an isomer or a mixture of isomers, where R ⁵ , R ⁶ , R ⁷ , R ¹⁴ and DB have the meanings given above, f 'is 1 or 2, V ^{1' is} selected from valcyltrulline, valyllisine, phenylalanyllysine, alanylphenylalanyllysine and D-alanylphenylalanyllysine, L ' selected from

q 'has values ranging from 1 to 20, rr, rr' and rr '' each independently has values ranging from 0 to 8, each of X ⁴⁰ and X ^{41 is} independently selected from O, S and NR ¹³⁵ , where R ^{135 is} selected from H and C _1-3 alkyl, each of uu, uu 'and uu''is independently selected from 0 and 1, Ab is an antibody or fragment or derivative thereof, and V ^{1 is} attached to an atom in DB and selected from mono-, di- or oligosaccharide or its derivative and

where R ¹⁴¹ , R ¹⁴² and R ^{143 are} independently selected from H and optionally substituted C _1-8 alkyl, C _1-8 heteroalkyl, C _3-8 cycloalkyl, C _1-8 heterocycloalkyl, C _5-8 aryl, or C _1-8 heteroaryl.

In yet another embodiment, the compound of formula ( III ) is provided

Synthesis of Compounds of the Invention

The compounds of formulas (I) to (IV) can be conveniently prepared by a method similar to some extent for the compounds described in WO 01/83448, WO 02/083180, WO 2004/043493, WO 2007/018431, WO 2007/089149 and WO 2009/017394.

In FIG. 2-4, the synthesis of some protected DA units is described. These DA protected units can usually be obtained from commercially available substituted benzaldehydes.

DB groups can usually be obtained in several stages from commercially available starting materials with good yield. Linking with suitable DA units allows the preparation of substances in several stages. The synthesis of indolysin-containing substances is described in FIG. 5 and 6. The synthesis of 7-azabenzofuran-containing substances is shown in FIG. 8. In FIG. 7 and 9 show the synthesis of two other DB units. Other syntheses are described in the Examples section.

Linker-agent conjugates can be prepared by combining a DB unit, a DA unit, and one or more progroups. The synthesis of linker-agent conjugates 114 , 115 and 116 is shown in FIG. 10, 11 and 12, respectively. Further examples of linker-agent conjugates are shown in FIG. 13.

In one embodiment, a compound of formula ( I ) or ( II ) is used to prepare a compound of formula ( III ). In another embodiment, a compound of formula ( I ) or ( II ) is used to prepare a compound of formula (IV) . In another embodiment, a compound of formula (IV) is used to prepare a compound of formula ( III ). In another embodiment, the compound of formula ( III ), where V ¹ is a protecting group, is used to produce another compound of formula ( III ), where V ¹ is an in vivo cleavable / convertible group.

Application, methods and compositions

In one aspect, the present invention relates to the use of a compound of formula ( I ) or ( II ) for the preparation of a compound of formula ( III ).

In another aspect, the present invention relates to the use of a compound of formula (IV) for the preparation of a compound of formula ( III ).

In another aspect, the present invention relates to the use of a compound of formula ( I ) or ( II ) for the preparation of a compound of formula (IV).

In another aspect, the present invention relates to the use of a compound of formula ( III ), wherein V ¹ is a protecting group for the preparation of another compound of formula ( III ), where V ¹ is an in vivo cleavable / convertible group.

In another aspect, the invention relates to the use of any of the compounds described above for the preparation of a pharmaceutical composition for treating a sick mammal. In one embodiment, the invention relates to the use of any of the compounds described above for the manufacture of a pharmaceutical composition for treating or preventing a tumor in a mammal.

The invention also relates to any compound as described above as a medicine or active ingredient or active substance in a medicine.

In an additional aspect, the invention relates to a method for producing a pharmaceutical composition comprising a compound as defined hereinabove, for preparing a solid or liquid composition for oral administration, topical administration or by injection. Such a method or process at least comprises the step of mixing the compound with a pharmaceutically acceptable carrier.

In one embodiment, the compound of the invention is used to treat or prevent a disease characterized by undesired proliferation. In another embodiment, the compound of the invention is used to treat or prevent a disease characterized by unwanted cell proliferation. In another embodiment, a compound of the invention is used to treat or prevent a tumor. In yet another embodiment, the compound of the invention is used to treat or prevent an inflammatory disease. In yet another embodiment, a compound of the invention is used to treat or prevent an autoimmune disease. In yet another embodiment, a compound of the invention is used to treat or prevent a bacterial, viral, or microbial infection.

In an additional embodiment, the present invention relates to a method for treating a mammal with a disease characterized by undesired (cell) proliferation using a compound of the present invention. In another embodiment, the present invention relates to a method for treating a mammal with a tumor using a compound of the present invention. In yet another embodiment, the present invention relates to a method for treating a mammal with an inflammatory disease using a compound of the present invention. In yet another embodiment, the present invention relates to a method for treating a mammal with an autoimmune disease using a compound of the present invention. In yet another embodiment, the present invention relates to a method for treating a mammal with a bacterial, viral or microbial infection using a compound of the present invention.

In a further embodiment, the invention relates to a method for treating a sick mammal, which comprises administering a pharmaceutical composition comprising a compound of the present invention to a mammal in a therapeutically effective dose.

In one embodiment, the invention relates to a method for treating or preventing a tumor in a mammal, which comprises administering a pharmaceutical composition comprising a compound of the present invention to a mammal in a therapeutically effective dose.

In another embodiment, the invention relates to a method for treating or preventing an inflammatory disease in a mammal, which comprises administering a pharmaceutical composition comprising a compound of the present invention to a mammal in a therapeutically effective dose.

In another embodiment, the invention relates to a method for treating or preventing an autoimmune disease in a mammal, which comprises administering a pharmaceutical composition comprising a compound of the present invention to a mammal in a therapeutically effective dose.

In another embodiment, the invention relates to a method for treating or preventing a bacterial, viral or microbial infection in a mammal, which comprises administering a pharmaceutical composition comprising a compound of the present invention to a mammal in a therapeutically effective dose.

The invention also relates to pharmaceutical compositions containing the compounds of the invention as defined hereinabove. The compound of the invention can be administered in purified form together with a pharmaceutical carrier in the form of a pharmaceutical composition. The preferred form depends on the intended route of administration and therapeutic use. The pharmaceutical carrier may be any compatible non-toxic substance suitable for the delivery of a compound of the invention to a patient. Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions, such as (sterile) water or buffered saline, or other solvents or carriers, such as glycols, glycerin, oils, such as olive oil or injectable organic esters, alcohol, fats, waxes and inert solids. A pharmaceutically acceptable carrier may further comprise physiologically acceptable compounds which, for example, stabilize or enhance the absorption of the compounds of the invention. Such physiologically acceptable compounds include, for example, carbohydrates such as glucose, sucrose or dextrans, antioxidants such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins, or other stabilizers or excipients. One skilled in the art should know that the choice of a pharmaceutically acceptable carrier, including a physiologically acceptable compound, depends, for example, on the mode of administration of the composition. Pharmaceutically acceptable adjuvants, buffers, dispersants, and the like. may also be included in pharmaceutical compositions.

For oral administration, the active ingredient can be administered in solid dosage forms, such as capsules, tablets and powders, or in liquid dosage forms, such as elixirs, syrups and suspensions. The active component (s) can be encapsulated in gelatin capsules together with inert ingredients and powdered carriers such as glucose, lactose, sucrose, mannitol, starch, cellulose or cellulose derivatives, magnesium stearate, stearic acid, sodium saccharin, talc, magnesium carbonate and the like. Examples of additional inert ingredients that can be added to provide the desired color, taste, stability, buffer capacity, dispersion or other known desired properties are red iron oxide, silica gel, sodium lauryl sulfate, titanium dioxide, edible white ink, and the like. Similar diluents can be used to form compressed tablets. And tablets and capsules can be prepared as sustained release products to provide sustained release of the drug over time. Pressed tablets may be coated with a sugar coating or film to mask any undesirable taste and protect the tablets from the atmosphere, or coated with an enteric coating for selective digestion in the gastrointestinal tract. Liquid dosage forms for oral administration may contain a colorant and a flavoring agent to improve patient perception.

However, the compounds of the invention are preferably administered parenterally. Preparations of the compounds of the invention for parenteral administration must be sterile. Sterilization is easily performed by filtration through membranes for sterilizing filtration, optionally before or after lyophilization and recovery. Parenteral administration of the compounds of the invention corresponds to known methods of administration, for example, intravenous, intraperitoneal, intramuscular, intra-arterial or intralesional injection or infusion. The compounds of the invention can be administered continuously by infusion or bolus injection. A typical composition for intravenous infusion can be obtained so that it contains from 100 to 500 ml of sterile 0.9% NaCl or 5% glucose, optionally with the addition of 20% albumin solution and from 1 mg to 10 g of the compound of the invention, depending on a particular type of compound of the invention and its desired dosage regimen Methods for preparing parenterally administered compositions are well known in the art and are described in more detail in various sources, including, for example, Remington's Pharmaceutical Science.

The compound of the invention can also be used in combination treatment in which the compound of the present invention is used in combination with one or more other therapeutic agents. A combination of two or more therapeutic agents may have a beneficial effect on treatment outcome. Agents may be administered either sequentially or concomitantly. Thus, in one embodiment, the present invention relates to the use of a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention in a combination treatment.

The invention is further illustrated by the following examples. These examples are provided for illustrative purposes only and do not limit the scope of the invention in any way.

EXAMPLES

Example 1

General method for the alkylation of compounds 2 and 6

To a suspension of NaH (2.5 equiv.) In DMF was added a solution of bromonaphthalene 2 or 6 in DMF and the resulting mixture was stirred for 1 hour at room temperature. Alken (1.6 equiv.) Was added and the mixture was stirred for another 2 hours at room temperature. The reaction was quenched slowly with saturated aqueous NH ₄ Cl and the resulting mixture was extracted with EtOAc. The organic layer was washed with water and brine, dried (Na ₂ SO ₄ ), filtered and concentrated. The crude product was purified by column chromatography to give alkylated naphthalene 3 or 7 .

General method for radical ring closure of compounds 3, 7, 11 and 15

A solution of naphthalene 3 , 7 , 11 or 15 in toluene was placed in a nitrogen atmosphere by bubbling nitrogen into the solution for 10 minutes, AIBN (0.25 equiv.) And TTMSS (1.1 equiv.) Were added and the mixture was stirred at a temperature of 80 ° C for 4 hours. The reaction mixture was cooled to room temperature, water was added, and the resulting mixture was extracted with EtOAc. The organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated. The crude product was recrystallized from heptane and then purified by column chromatography to give compound 4 , 8 , 12 or 16 as a racemic mixture. Enantiomers were separated by chiral HPLC (Chiralpak IA, heptanes / DCM).

Compound 4a : ¹ H NMR (300 MHz, CDCl ₃ ), δ (ppm): 1.61 (9 H, s, Boc), 3.11 (1 H, t, J = 9.9 Hz, H-10), 3.52 (1 H, d, J = 9.9 Hz, H-10), 3.98 (1 H, ddd, J = 1.5 Hz, 7.3 Hz, 11.1 Hz, H-2), 4.08 (1 H, m, H-1), 4.30 (1 H, d, J = 11.1 Hz, H-2), 5.28 (2 H, s , OC H ₂ Ph), 7.30-7.55 (6 H, m, OCH ₂ Ph , H-7), 7.97 (1 H, d, J = 6.9 Hz, H-6), 8.06 (1 H, broad s, H-4); 8.58 (1 H, d, J = 8.4 Hz, H-8);

Compound 4b : ¹ H NMR (300 MHz, CDCl ₃ ), δ (ppm): 1.61 (9 H, s, Boc), 3.42 (1 H, t, J = 10.0 Hz, H-10), 3.91 (1 H, d, J = 10.0 Hz, H-10), 4.00-4.10 (2 H, m, H-1, H-2), 4, 29 (1 H, d, J = 10.2 Hz, H-2), 5.26 (2 H, s, OC H ₂ Ph), 7.10-7.55 (7 H, m, OCH ₂ Ph , H-7, H-8), 7.92 (1 H, br s, H-4), 8.06 (1 H, d, J = 8.1 Hz, H-6);

Compound 4c : ¹ H NMR (300 MHz, CDCl ₃ ), δ (ppm): 1.61 (9 H, s, Boc), 3.50 (1 H, dd, J = 9.2 Hz, 11.2 Hz, H-10), 3.97 (1 H, dd, J = 2.8 Hz, 11.2 Hz, H-10), 4.08 (1 H, dd, J = 8.4 Hz, 11.8 Hz, H-2), 4.34 (1 H, d, J = 11.8 Hz, H-2), 4.55-4.65 (1 H, m, H-1) 5.27 (2 H, s, OC H ₂ Ph), 7.33 (1 H, dd, J = 7.2 Hz, 8.4 Hz, H-7), 7.35-7.55 ( 5 H, m, OCH ₂ Ph ), 7.91 (1 H, dd, J = 1.3 Hz, 7.2 Hz, H-6), 8.00 (1 H, broad s, H-4 ), 8.55 (1 H, dd, J = 1.3 Hz, 8.4 Hz, H-6);

Compound 4d : ¹ H NMR (300 MHz, CDCl ₃ ), δ (ppm): 1.29 (3 H, t, J = 7.2 Hz, 9-CH ₃ ), 1.61 (9 H , s, Boc), 2.96 (1 H, m, 9-CH ₂ ), 3.19 (1 H, m, 9-CH ₂ ), 3.23 (1 H, t, J = 10.6 Hz, H-2a), 3.60 (1 H, m, H-2b), 3.99 (2 H, m, H-10), 4.30 (1 H, d, J = 10.6 Hz , H-1), 5.26 (2 H, s, OC H ₂ Ph), 7.23-7.45 (7 H, m, 7-H, 8-H, OCH ₂ Ph ), 7.91 (1 H, broad s, H-4), 8.25 (1 H, m, H-6);

Compound 4e : ¹ H NMR (300 MHz, CDCl ₃ ), δ (ppm): 1.64-1.57 (12 H, m, C (CH ₃ ) ₃ , 10-CH ₃ ), 3, 88-4.00 (4 H, m, 9-OCH ₃ , H-2a), 4.17 (1 H, dt, J = 9.3, 2.3 Hz, H-1), 4.28 ( 1 H, broad s, J = 9.6 Hz, H-2b), 4.53 (1 H, dq, J = 7.1, 1.9 Hz, H-10), 5.25 (2 H, s, OC H ₂ Ph), 6.81 (1 H, d, J = 7.7 Hz, H-8), 7.20 (1 H, t, J = 8.1 Hz, H-7 ), 7.30-7.60 (5 H, m, OCH ₂ Ph ), 7.91 (1 H, d, J = 8.6 Hz, H-6), 7.96 (1 H, broad. s, H-4);

Compound 4f : ¹ H NMR (300 MHz, CDCl ₃ ), δ (ppm): 1.57 (3 H, t, CH ₂ C H ₃ ), 1.60 (9 H, s, (CH ₃ ) ₃ ), 3.30 (1 H, dd), 3.97 (2 H, m), 4.16 (2 H, dd, J = 1.5 Hz, 7.2 Hz), 4.28 ( 2 H, q, C H ₂ CH ₃ ), 5.25 (2 H, s, OC H ₂ Ph), 6.82 (1 H, d, J = 7.5 Hz, H-8), 7, 20 (1 H, dd, J = 7.8 Hz, 8.4 Hz, H-7), 7.37-7.54 (3 & 2 H, 2 × m, OCH ₂ Ph ), 7.87 ( 1 H, d, J = 8.4 Hz, H-6), 7.89 (1 H, broad s, H-4); MS (ESI) mass / charge = 468 [M + H] ⁺ ;

Compound 4g : ¹ H NMR (300 MHz, CDCl ₃ ), δ (ppm): 1.12 (3 H, OCH ₂ CH ₂ C H ₃ ), 1.60 (9 H, s, (CH ₃ ) ₃ ), 1.98 (2 H, m, OCH ₂ C H ₂ CH ₃ ), 3.29 (1 H, dd), 3.97 (3 H, m), 4.06 (1 H, m ), 4.29 (2 H, m), 5.24 (2 H, s, OC H ₂ Ph), 6.81 (1 H, d, J = 7.8 Hz, H-8), 7, 19 (1 H, J = 7.8 Hz, 8.4 Hz, H-7), 7.33-7.54 (3 & 2 H, 2 × m, OCH ₂ Ph ), 7.87 (1 H d, J = 8.4 Hz, H-6), 7.89 (1 H, broad s, H-4);

Compound 4h : ¹ H NMR (300 MHz, CDCl ₃ ), δ (ppm): 1.49 (6 H, dd, J = 5.7 Hz, 10.8 Hz, 2 × CH ₃ ), 1 60 (9 H, s, Boc), 3.29 (1 H, t, J = 10.5 Hz, H-10a), 3.91-4.02 (2 H, m, H-1, H -10b), 4.22-4.36 (2 H, m, H-2a, H-2b), 4.74-4.82 (1 H, m, OCH), 5.25 (2 H, s , OC H ₂ Ph), 6.83 (1 H, d, J = 7.5 Hz, H-8), 7.16-7.58 (6 H, m, H-7, OCH ₂ Ph ), 7.82-7.91 (2 H, m, H-6, H-4);

Compound 4i : ¹ H NMR (300 MHz, CDCl ₃ ), δ (ppm): 1.61 (9 H, s, (CH ₃ ) ₃ ), 3.31 (1 H, t), 3, 99 (2 H, m), 4.31 (1 H, d), 4.60 (1 H, m), 5.25 (2 H, s, OC H ₂ Ph), 7.19 (1 H, dd), 7.39-7.55 (6 H, m), 7.96 (1 H, br s, H-4), 8.25 (1 H, d);

Compound 4j : ¹ H NMR (300 MHz, CDCl ₃ ), δ (ppm): 1.60 (9 H, s, (CH ₃ ) ₃ ), 3.31 (1 H, dd, J = 10 , 2 Hz), 3.90-4.00 (2 H, m), 3.96 (3 H, s, OCH ₃ ), 4.25 (2 H, m), 5.24 (2 H, s , OC H ₂ Ph), 6.83 (1 H, d, J = 7.5 Hz, H-8), 7.20 (1 H, dd, J = 7.8 Hz, 8.4 Hz, H -7), 7.34-7.54 (3 & 2 H, 2 × m, OCH ₂ Ph ), 7.87 (1 H, d, H-6), 7.89 (1 H, broad s , H-4);

Compound 4k : ¹ H NMR (400 MHz, CDCl ₃ ), δ (ppm): 1.56-1.61 (12 H, m, Boc, 10-CH ₃ ), 2.69 (3 H, s, 9-CH ₃ ), 3.99-4.08 (2 H, m, H-2, H-10), 4.18-4.3 (2 H, m, H-2, H-1 ), 5.26 (2 H, br s, OC H ₂ Ph), 7.18-7.28 (2 H, m, Ar-H), 7.34-7.44 (3 H, m, Ar-H), 7.54 (2 H, d, J = 6.5 Hz, Ar-H), 7.97 (1 H, br s, H-4), 8.23 (1 H, d , J = 7.8 Hz, H-8); MS (ESI) mass / charge = 396 [M + H] ⁺ ;

Compound 8a : ¹ H NMR (300 MHz, CDCl ₃ ), δ (ppm): 1.60 (9 H, s, Boc), 3.28-3.44 (3 H, m, dihydrofuran + H -2), 3.96-4.18 (3 H, m, H-2, H-1, H-10), 4.22-4.32 (1 H, m, H-10), 4, 73 (2 H, dt, J = 1.8, 9.0 Hz, dihydrofuran), 5.24 (2 H, s, OC H ₂ Ph), 7.18 (1 H, d, J = 8.4 Hz, H-7), 7.30-7.55 (5 H, m, OCH ₂ Ph ), 7.81 (1 H, br s, H-4), 7.81 (1 H, d, J = 8.4 Hz, H-6);

Compound 8b : ¹ H NMR (400 MHz, CDCl ₃ ), δ (ppm): 1.55-1.66 (12 H, m, Boc + 10-Me), 3.26-3.42 ( 2 H, m, dihydrofuran), 3.92-4.02 (2 H, m, H-2), 4.22-4.34 (1 H, m, H-1), 4.60-4, 72 (3 H, m, dihydrofuran + H-10), 5.25 (2 H, s, OC H ₂ Ph), 7.17 (1 H, d, J = 8.4 Hz, H-7), 7.32-7.58 (5 H, m, OCH ₂ Ph ), 7.83 (1 H, broad s, H-4), 7.84 (1 H, d, J = 8.4 Hz, H-6);

Compound 8c : ¹ H NMR (300 MHz, CDCl ₃ ), δ (ppm): 1.60 (9 H, s, Boc), 3.38-3.47 (1 H, m, H-2 ), 3.94-4.11 (3 H, m, H-2, H-1, H-10), 4.22-4.31 (1 H, m, H-10), 5.24 ( 2 H, s, OC H ₂ Ph), 6.09 (1 H, d, J = 1.5 Hz, dioxymethylene), 6.15 (1 H, d, J = 1.5 Hz, dioxymethylene), 7 00 (1 H, d, J = 8.9 Hz, H-7), 7.32-7.56 (5 H, m, OCH ₂ Ph ), 7.70 (1 H, broad s, H -4), 7.87 (1 H, d, J = 8.9 Hz, H-6);

Compound 8d : ¹ H NMR (400 MHz, CDCl ₃ ), δ (ppm): 1.56-1.64 (12 H, m, Boc + 10-Me), 3.85-3.90 ( 1 H, m, H-2), 3.96-4.04 (1 H, m, H-2), 4.23-4.33 (1 H, m, H-1), 4.58- 4.66 (1 H, m, H-10), 5.24 (2 H, s, OC H ₂ Ph), 6.07 (1 H, d, J = 1.3 Hz, dioximethylene), 6, 12 (1 H, d, J = 1.3 Hz, dioximethylene), 7.00 (1 H, d, J = 8.9 Hz, H-7), 7.32-7.56 (5 H, m , OCH ₂ Ph ), 7.75 (1 H, br s, H-4), 7.89 (1 H, d, J = 8.9 Hz, H-6);

Compound 12: ^oneH NMR (300 MHz, CDCl₃), δ (ppm): 1.60 (9 H, s, Boc), 3.32 (1 H, t,J= 10.2 Hz, H-10), 3.86-4.01 (2 H, m, H1, H-10), 3.99 (3 H, s, OMe), 4.18-4.30 (3 H, m, H-2, H-Fmoc), 4.53 (2 H, d,J= 6.8 Hz, H-Fmoc), 5.21 (2 H, s, OCH ₂Ph), 6.82 (1 H, br s, NH), 7.28-7.55 (11 H, m, OCH₂ Ph, H-Fmoc), 7.61 (1 H, s, H-8), 7.64 (1 H, s, H-6), 7.90 (1 H, broad s, H-4);

Compound 16 : ¹ H NMR (300 MHz, CDCl ₃ ), δ (ppm): 1.61 (9 H, s, Boc), 3.26 (1 H, t, J = 9.9 Hz, H-10a), 3.77 (3 H, s, OMe), 3.86-3.99 (2 H, m, H-10b, H-2a), 4.06-4.13 (1 H, m, H-1), 4.24-4.34 (2 H, m, H-2b, H-Fmoc), 4.60 (2 H, d, J = 6.9 H, H-Fmoc), 5.25 (2 H, s, OC H ₂ Ph), 7.26-7.45 (8 H, m), 7.50-7.54 (2 H, d), 7.64 (2 H, d), 7.78 (2 H, d), 8.04-8.10 (2 H, m).

Example 2

General method for deprotecting amine, condensation and debenzylation

The N-Boc-O-Bn-protected seco CBI derivative was dissolved in 4 M HCl / dioxane and stirred at ambient temperature until TLC indicated completion of the reaction. The reaction mixture was concentrated in vacuo and then dried in high vacuum. The residue was dissolved in dry DMF, the solution was cooled to 0 ° C, and EDC (2.0 equiv.) And a functionalized, optionally Boc-protected indole-2-carboxylate (1.5 equiv.) Were added. The reaction mixture was allowed to warm to ambient temperature overnight, after which it was concentrated in vacuo. The residue was treated with water / EtOAc, a saturated aqueous NaHCO ₃ solution was added, and the mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. Flash chromatography afforded a benzyl protected agent. This compound was dissolved in methanol and Pd / C (10% Pd, 0.2 equiv.) And HCOONH ₄ (10 equiv.) Were added. The reaction mixture was stirred at 40 ° C until TLC showed completion of the reaction. The reaction mixture was cooled to room temperature and filtered through a pad of celite. Celite was washed thoroughly with MeOH, and the combined filtrate was concentrated in vacuo. Flash chromatography afforded a pure agent, optionally still protected by a Boc group. Removal of this Boc group was carried out by dissolving the compound in 4 M HCl in dioxane. The mixture was stirred until TLC showed completion of the reaction. The reaction mixture was concentrated to obtain pure compound.

Compound 17 : ¹ H NMR (CD ₃ OD, 400 MHz), δ (ppm): 3.46 (1 H, m), 3.94-3.99 (4 H, m), 4.38 (1 H, m), 4.57 (1 H, m), 4.69 (1 H, m), 6.95 (1 H, d, J = 8 Hz), 7.14 (1 H, s ), 7.26 (1 H, t, J = 8 Hz), 7.52 (2 H, m), 7.79 (1 H, d, J = 8 Hz), 7.85 (1 H, broad c), 8.11 (1 H, s), 8.37 (1 H, s); MS (ESI) mass / charge = 517 [M + H] ⁺ ;

Compound 18 : ¹ H NMR (300 MHz, DMSO-d ₆ ), δ (ppm): 3.44-3.50 (4 H, m, H-2``, H-3 ''), 3.62 (1 H, dd, J = 8.1 Hz, 10.4 Hz, H-10), 3.88 (2 H, t, J = 5.0 Hz, H-4``), 3 88-3.98 (4 H, m, H-10, OMe), 3.93-4.00 (4 H, m, H-10, OMe), 4.27-4.37 (1 H, m, H-1), 4.54 (d, J = 10.4 Hz, H-2), 4.60-4.75 (3 H, m, H-1 '', H-2), 7 , 00 (1 H, d, J = 7.8 Hz, H-8), 7.17 (1 H, d, J = 1.3 Hz, H-3 '), 7.28 (1 H, dd , J = 7.8 Hz, 8.2 Hz, H-7), 7.45 (1 H, d, J = 8.9 Hz, H-7 '), 7.64 (1 H, dd, J = 1.9 Hz, 8.9 Hz, H-6 '), 7.71 (1 H, d, J = 8.2 Hz, H-6), 8.00 (1 H, s, H-4 ), 8.21 (1 H, d, J = 1.5 Hz, H-4 '), 8.69 (1 H, s, triazolyl-H), 10.32 (1 H, s, NH), 10.40 (1 H, s, OH), 11.70 (1 H, s, NH), MS (ESI) mass / charge = 605 [M + H] ⁺ ;

Compound 19 : ¹ H NMR (300 MHz, CDCl ₃ ), δ (ppm): 3.5 (12 H, m), 3.9 (3 H, t, J = 4.2 Hz), 4 , 0 (3 H, s, 9-OCH ₃ ), 4.3 (1 H, t, J = 7.6 Hz, H-2a), 4.5 (1 H, d, J = 11.0 Hz , H-2b), 4.6 (4 H, t, J = 4.8 Hz), 6.6 (2 H, d, J = 8.2 Hz), 7.0 (1 H, d, J = 8.2 Hz, H-8), 7.2 (1 H, s, H-3 '), 7.3 (1 H, t, J = 7.6 Hz, H-7), 7.5 (1 H, d, J = 9.0 Hz, H-6 '), 7.6 (2 H, d, J = 8.5 Hz), 7.6 (1 H, d, J = 9.0 Hz), 7.7 (1 H, d, J = 8.2 Hz, H-6), 8.0 (2 H, s, CH), 8.2 (1 H, s, H-4), 8.7 (1 H, s, H-4 '), 10.3 (1 H, s, NH), 10.4 (1 H, s, NH), 11.7 (1 H, s, NH) ; MS (ESI) mass / charge = 811.3 [M + H] ⁺ ;

Compound 20 : ¹ H NMR (300 MHz, DMSO-d6), δ (ppm): 2.94 (2 H, sextet, C H ₂ NH ₃ ), 3.48-3.66 (15 H, m, CH ₂ ), 3.89 (2 H, t, CH ₂ ), 3.92-4.03 (4 H, m), 4.33 (1 H, t, J = 7.5 Hz), 4.53 (1 H, d, J = 11 Hz), 4.65 (2 H, t, J = 4.6 Hz), 4.72 (1 H, d, J = 15 Hz), 7.0 (1 H, d, J = 7.5 Hz), 7.18 (1 H, s), 7.28 (1 H, t, J = 8.1 Hz), 7.46 (1 H, d, J = 8 Hz), 7.64 (1 H, d, J = 9.9 Hz), 7.71 (1 H, d, J = 9.3 Hz), 7.93 (3 H, s), 8.00 (1 H, s), 8.2 (1 H, s), 8.7 (1 H, s), 10.3 (1 H, s), 10.4 (1 H, s), 11.7 (1 H, s);

Compound 21 : ¹ H NMR (300 MHz, CD ₃ OD), δ (ppm): 3.48-3.64 (13 H, m), 3.95 (2 H, m, (C = O ) - CH ₂ ), 4.00 (4 H, m, OCH ₃ , H-10), 4.40 (1 H, m, H-1), 4.68 (5 H, m, H-2 + (C = O) CH ₂ CH ₂ ), 6.97 (1 H, d, J = 7.3 Hz), 7.17 (1 H, s), 7.28 (1 H, t, J = 7 , 9 Hz), 7.53 (2 H, m), 7.80 (1 H, d, J = 8.2 Hz), 7.84 (1 H, m), 8.13 (1 H, s ), 8.55 (1 H, s); MS (ESI) mass / charge = 707.3 [M + H] ⁺ , 729.3 [M + Na] ⁺ .

Example 3

Compound 30 : ¹ H NMR (400 MHz, DMSO-d ₆ ), δ (ppm): 2.76 (3 H, s, 9-Me), 3.50 (1 H, m, H-10 ), 3.78 (1 H, d, J = 10.8 Hz, H-10), 4.00-4.10 (4 H, m, H-1, NCH ₃ ), 4.13-4, 20 (1 H, m, H-2), 4.33-4.39 (1 H, m, H-2), 7.19-7.28 (3 H, m, H7, Ph-H), 7.33 (1 H, d, J = 7.0 Hz, H-8), 7.45 (1 H, s, H-3 '), 7.58-7.75 (3 H, m, H -4, H6 ', H7'), 7.85 (2 H, d, J = 8.6 Hz, Ph-H), 8.02 (1 H, d, J = 8.0 Hz, H-6 ), 8.06 (1 H, s, H-4 '), 9.45 (2 H, broad s, NH ₂ ), 10.38 (1 H, s, OH), 10.52 (1 H , s, NH); MS (ESI) mass / charge = 539 [M + H] ⁺ .

Example 4

Compound 32 : ¹ H NMR (300 MHz, DMSO), δ (ppm): 2.75 (3 H, s, 9-Me), 3.51 (1 H, t, J = 9.0 Hz , H-10), 3.77 (1 H, d, J = 11.7 Hz, H-10), 4.06 (1 H, m, H-2), 4.17 (1 H, t, J = 9.9 Hz, H-2), 4.34-4.39 (1 H, m, H-1), 7.10 (2 H, d, J = 8.7 Hz, H-2 ''), 7.21 (1 H, t, J = 6.9 Hz, H-7), 7.32 (1 H, d, J = 6.9 Hz, H-8), 7.49-7 , 61 (4 H, m, H-4, H-3 ', H-6', H-7 '), 7.75 (2 H, d, J = 8.7 Hz, H-1``) 8.02 (1 H, d, J = 7.8 Hz, H-6), 8.06 (1-H, s, H-4 '), 10.31 (1 H, s, NH), 10.37 (1 H, s, OH); 12.03 (1 H, s, NH); MS (ESI) mass / charge = 525.2 [M + H] ⁺ ;

Compound 37 : ¹ H NMR (300 MHz, DMSO), δ (ppm): 2.75 (3 H, s, 9-Me), 3.51 (1 H, t, J = 10.5 Hz , H-10), 3.77 (1 H, d, J = 10.8 Hz, H-10), 4.06 (1 H, d, J = 9.9 Hz, H-2), 4, 16 (1 H, t, J = 10.5 Hz, H-2), 4.33-4.39 (1 H, m, H-1), 6.77 (2 H, d, J = 9, 0 Hz, H-2``), 7.21 (1 H, t, J = 7.2 Hz, H-7), 7.32 (1 H, d, J = 6.6 Hz, H-8 ), 7.44-7.61 (6 H, m, H-4, H-3 ', H-6', H-7 ', H-1''), 8.00-8.04 (2 H, m, H-6, H-4 '), 9.27 (1 H, s, OH), 10.11 (1 H, s, NH), 10.36 (1 H, s, OH), 11.99 (1 H, s, NH); MS (ESI) mass / charge = 526.3 [M + H] ⁺ ;

Compound 38 : ¹ H NMR (300 MHz, DMSO), δ (ppm): 2.76 (3 H, s, 9-Me), 3.47-3.56 (5 H, m, H- 10), 3.73-3.79 (3 H, m, H-10), 4.03-4.10 (3 H, m, H-2), 4.16 (1 H, t, J = 7.8 Hz, H-2), 4.33-4.39 (1 H, m, H-1), 4.62 (1 H, m, OH), 6.97 (2 H, d, J = 9.0 Hz, H-2``), 7.23 (1 H, t, J = 7.8 Hz, H-7), 7.32 (1 H, d, J = 6.9 Hz, H-8), 7.49-7.58 (4 H, m, H-4, H-3 ', H-6', H-7 '), 7.72 (2 H, d, J = 9 , 0 Hz, H-1 ''), 8.00-8.05 (2 H, m, H-6, H-4 '), 10.23 (1 H, s, NH), 10.36 ( 1 H, s, OH); 12.04 (1 H, s, NH); MS (ESI) mass / charge = 614.5 [M + H] ⁺ ;

Compound 39 : ¹ H NMR (300 MHz, DMSO), δ (ppm): 2.76 (3 H, s, 9-Me), 3.39-3.58 (13 H, m, H- 10), 3.73-3.79 (3 H, m, H-10), 4.04-4.10 (3 H, m, H-2), 4.16 (1 H, t, J = 9.0 Hz, H-2), 4.33-4.39 (1 H, m, H-1), 4.57 (1 H, t, J = 5.4 Hz, OH), 6.98 (2 H, d, J = 9.0 Hz, H-2``), 7.22 (1 H, t, J = 7.2 Hz, H-7), 7.31 (1 H, d, J = 6.9 Hz, H-8), 7.48-7.58 (4 H, m, H-4, H-3 ', H-6', H-7 '), 7.71 (2 H, d, J = 9.0 Hz, H-1 ''), 8.00-8.05 (2 H, m, H-6, H-4 '), 10.22 (1 H, s, NH) 10.36 (1 H, s, OH); 12.03 (1 H, s, NH); MS (ESI) mass / charge = 724.5 [M + H] ⁺ ;

Compound 42 : ¹ H NMR (300 MHz, DMSO), δ (ppm): 2.76 (3 H, s, 9-Me), 3.24 (3 H, s, OMe), 3.40 -3.61 (13 H, m, H-10), 3.73-3.80 (3 H, m, H-10), 4.04-4.10 (3 H, m, H-2) , 4.17 (1 H, t, J = 7.8 Hz, H-2), 4.34-4.40 (1 H, m, H-1), 6.97 (2 H, d, J = 9.0 Hz, H-2``), 7.21 (1 H, t, J = 6.6 Hz, H-7), 7.32 (1 H, d, J = 6.6 Hz, H-8), 7.49-7.58 (4 H, m, H-4, H-3 ', H-6', H-7 '), 7.71 (2 H, d, J = 9 , 0 Hz, H-1 ''), 8.00-8.05 (2 H, m, H-6, H-4 '), 10.21 (1 H, s, NH), 10.37 ( 1 H, s, OH); 12.02 (1 H, s, NH); MS (ESI) mass / charge = 738.5 [M + H] ⁺ ;

Compound 43 : ¹ H NMR (300 MHz, DMSO), δ (ppm): 2.76 (3 H, s, 9-Me), 3.51 (1 H, m, H-10), 3 78 (1 H, m, H-10), 4.6 (1 H, d, J = 10.5 Hz, H-2), 4.17 (1 H, t, J = 8.1 Hz, H-2), 4.34-4.37 (1 H, m, H-1), 6.72 (1 H, m, H-4``), 7.12-7.79 (9 H, m, H-7, H-8, H-4, H-3 ', H-6', H-7 ', H-2'', H-3``, H-6''), 8, 00-8.05 (2 H, m, H-6, H-4 '), 10.39 (2 H, s, NH, OH), 12.12 (1 H, s, NH); MS (ESI) mass / charge = 525.6 [M + H] ⁺ ;

Compound 44 : ¹ H NMR (300 MHz, DMSO), δ (ppm): 2.76 (3 H, s, 9-Me), 3.39-3.62 (13 H, m, H- 10), 3.75-3.79 (3 H, m, H-10), 4.04-4.21 (4 H, m, H-2, H-2), 4.33-4.37 (1 H, m, H-1), 4.55 (1 H, br.s, OH), 6.72 (1 H, m, H-4``), 7.20-7.33 (3 H, m, H-7, H-8, H-3``), 7.41 (1 H, d, J = 8.1 Hz, H-2 ''), 7.50-7.59 ( 5 H, m, H-4, H-3 ', H-6', H-7 ', H-6''), 8.00-8.06 (2 H, m, H-6, H- 4 '), 10.26 (1 H, s, NH), 10.37 (1 H, s, OH), 12.05 (1 H, s, NH); MS (ESI) mass / charge = 702.7 [M + H] ⁺ ;

Compound 45 : ¹ H NMR (300 MHz, DMSO), δ (ppm): 2.75 (3 H, s, 9-Me), 3.51 (1 H, t, J = 10.2 Hz , H-10), 3.77 (1 H, d, J = 10.2 Hz, H-10), 4.04 (1 H, m, H-2), 4.18 (1 H, m, H-2), 4.34-4.39 (1 H, m, H-1), 7.04 (2 H, m, NH ₂ ), 7.17-7.24 (3 H, m, H -7, H-2``), 7.30-7.35 (3 H, m, H-8, H-4 ', H-5'), 7.51-7.54 (3 H, m , H-3 ', H-1''), 7.30-7.80 (2 H, m, 4-H, H-7'), 8.01 (1 H, d, J = 8.4 Hz, H-6), 10.41 (2 H, m, OH, NH), 12.14 (1 H, s, NH); MS (ESI) mass / charge = 525.3 [M + H] ⁺ ;

Compound 46 : ¹ H NMR (300 MHz, DMSO), δ (ppm): 2.75 (3 H, s, 9-Me), 3.37-3.59 (17 H, m, H- 10), 3.73 (1 H, d, J = 10.2 Hz, H-10), 4.04 (1 H, d, J = 11.1 Hz, H-2), 4.16 (1 H, t, J = 7.8 Hz, H-2), 4.32-4.38 (1 H, m, H-1), 4.56 (1 H, t, J = 5.4 Hz, OH), 7.19-7.26 (2 H, m, H-7, H-3 '), 7.31 (1 H, d, J = 7.2 Hz, H-8), 7.46 -7.54 (3 H, m, H-4, H-6 ', H-7'), 7.98-8.03 (2 H, m, H-6, H-4 '), 8, 64 (1 H, t, J = 5.7 Hz, NH); 10.35 (1 H, s, OH); 11.88 (1 H, s, NH); MS (ESI) mass / charge = 610.5 [M + H] ⁺ .

Example 5

Compound 31 : ¹ H NMR (400 MHz, DMSO-d ₆ ), δ (ppm): 2.79 (3 H, s, 9-Me), 3.45-3.55 (5 H, m , H-10, 2 × OCH ₂ ), 3.75-3.80 (3 H, m, H-10, OCH ₂ ), 4.08 (1 H, d, J = 11.0 Hz, H- 2), 4.13-4.19 (3 H, m, H-1, OCH ₂ ), 4.36 (1 H, dd, J = 7.3 Hz, J = 10.8 Hz, H-2 ), 4.63 (1H, s, OH), 6.90 (1H, d, J = 2.0 Hz, H-3 '), 7.07 (2 H, d, J = 8.9 Hz, Ph-H), 7.21 (1 H, dd, J = 7.0 Hz, J = 8.3 Hz, H-7), 7.32 (1 H, d, J = 7.0 Hz, H -8), 7.37 (1 H, dd, J = 1.5 Hz, J = 8.4 Hz, H-7 '), 7.47 (1 H, d, J = 8.5 Hz, H -6 '), 7.56 (1 H, s, H-4), 7.80-7.85 (3H, m, Ph-H, H-4'), 8.01 (1 H, d, J = 8.4 Hz, H-6), 10.34 (1 H, s, OH), 11.74 (1 H, s, NH); MS (ESI) mass / charge = 571 [M + H] ⁺ ;

Compound 48 : ¹ H NMR (300 MHz, DMSO), δ (ppm): 2.75 (3 H, s, 9-Me), 3.48 (1 H, t, J = 10.2 Hz , H-10), 3.77 (1 H, d, J = 10.2 Hz, H-10), 4.08 (1 H, d, J = 10.5 Hz, H-2), 4, 17 (1 H, t, J = 8.1 Hz, H-2), 4.34-4.39 (1 H, m, H-1), 6.81 (1 H, s, H-3 ' ), 6.87 (2 H, d, J = 8.7 Hz, H-2``), 7.20 (1 H, t, J = 6.9 Hz, H-7), 7.30- 7.37 (2 H, m, H-8, H-7 '), 7.45 (1 H, d, J = 8.4 Hz, H-6'), 7.55 (1 H, broad. s, H-4), 7.71 (2 H, d, J = 8.7 Hz, H-1 ''), 7.82 (1-H, s, H-4 '), 8.01 ( 1 H, d, J = 8.4 Hz, H-6), 9.69 (1 H, s, OH), 10.35 (1 H, s, OH), 11.66 (1 H, s, NH); MS (ESI) mass / charge = 483.4 [M + H] ⁺ ;

Compound 49 : ¹ H NMR (300 MHz, DMSO), δ (ppm): 2.76 (3 H, s, 9-Me), 3.50 (1 H, t, J = 9.6 Hz , H-10), 3.77 (1 H, d, J = 11.1 Hz, H-10), 4.08 (1 H, d, J = 11.1 Hz, H-2), 4, 17 (1 H, t, J = 7.8 Hz, H-2), 4.31-4.37 (1 H, m, H-1), 6.81 (1 H, s, H-3 ' ), 6.88 (2 H, d, J = 8.7 Hz, H-2``), 7.20 (1 H, t, J = 7.2 Hz, H-7), 7.21 - 7.32 (2 H, m, H-8, H-4 '), 7.51-7.59 (2 H, m, H-4, H-5'), 7.65 (1 H, s , H-7 '), 7.72 (2 H, d, J = 8.7 Hz, H-1``), 8.01 (1 H, d, J = 8.4 Hz, H-6) 9.71 (1 H, s, OH); 10.35 (1 H, s, OH); 11.65 (1 H, s, NH); MS (ESI) mass / charge = 483.4 [M + H] ⁺ ;

Compound 50 : ¹ H NMR (300 MHz, DMSO), δ (ppm): 2.76 (3 H, s, 9-Me), 2.86 (6 H, s, N- (CH ₃ ) ₂ ), 3.51 (1 H, m, H-10, NCH ₂ ), 3.77 (1 H, m, H-10), 4.07 (1 H, m, H-2), 4, 16 (1 H, m, H-2), 4.34-4.42 (3 H, m, H-1, OCH ₂ ), 6.81 (1 H, m, H-3 '), 6, 87 (2 H, m, H-2``), 7.20 (1 H, m, H-7), 7.30-7.37 (2 H, m, H-8, H-7 ') 7.45 (1 H, m, H-6 '), 7.55 (1 H, broad s, H-4), 7.86 (3 H, m, H-4', H-1 ''), 8.01 (1 H, m, H-6), 10.35 (1 H, s, OH), 11.80 (1 H, s, NH); MS (ESI) mass / charge = 554.5 [M + H] ⁺ ;

Compound 51 : ¹ H NMR (300 MHz, DMSO-D ₆ ), δ (ppm): 2.72 (3 H, s, 9-Me), 2.81 (6 H, s, N (CH ₃ ) ₂ ), 3.17 (2 H, m, NCH ₂ ), 3.78 (1 H, d, H-10), 4.05 (1 H, d, H-2), 4.16 ( 1 H, t, H-2), 4.32 (1 H, t, H-1), 4.39 (2 H, t, OCH ₂ ), 6.89 (1 H, s), 7.12 (2 H, d), 7.20 (1 H, t), 7.28 (2 H, t), 7.58 (2 H, d), 7.67 (1 H, s), 7.88 (2 H, d), 8.00 (1 H, d, J = 8.2 Hz, H-6), 10.36 (1 H, s, OH), 11.88 (1 H, s, NH ); MS (ESI) mass / charge = 554.7 [M + H] ⁺ ;

Compound 52 : ¹ H NMR (300 MHz, DMSO), δ (ppm): 2.76 (3 H, s, 9-Me), 3.47-3.56 (4 H, m, H- 10), 3.76-3.81 (3 H, m, H-10), 4.07 (1 H, d, J = 10.8 Hz, H-2), 4.14-4.20 ( 3 H, m, H-2), 4.34-4.36 (1 H, m, H-1), 4.62-4.66 (1 H, m, OH), 6.91-6, 95 (1 H, m, H-4 ''), 7.06 (1 H, s, H-3 '), 7.21 (1 H, t, J = 6.9 Hz, H-7), 7.31 (1 H, d, J = 6.6 Hz, H-8), 7.36-7.42 (2 H, m, H-6 ', H-6``), 7.47- 7.58 (4 H, m, H-4, H-7 ', H-2``, H-3''), 7.88 (1 H, s, H-4'), 8.02 ( 1 H, d, J = 8.1 Hz, H-6), 10.35 (1 H, s, OH), 11.83 (1 H, s, NH); MS (ESI) mass / charge = 571.5 [M + H] ⁺ ;

Compound 53 : ¹ H NMR (300 MHz, DMSO-D ₆ ), δ (ppm): 2.73 (3 H, s, 9-Me), 3.49 (4 H, m, 2 CH ₂ ), 3.78 (3 H, CH ₂ ), 4.11 (4 H, m, CH ₂ ), 4.31 (1 H, dd), 4.59 (1 H, t), 6.87 ( 1 H, s), 7.04 (2 H, t), 7.17 (1 H, t), 7.28 (2 H, t), 7.58 (2 H, d), 7.64 ( 1 H, s), 7.81 (2 H, d), 8.00 (1 H, d, J = 7.7 Hz, H-6), 10.33 (1 H, s, OH), 11 70 (1 H, s, NH); MS (ESI) mass / charge = 571.7 [M + H] ⁺ ;

Compound 54 : ¹ H NMR (300 MHz, DMSO-D ₆ ), δ (ppm): 2.73 (3 H, s, 9-Me), 3.76 (2 H, m), 4, 07 (1 H, dd), 4.13 (1 H, t), 4.32 (1H, t), 6.74 (3 H, m), 7.18 (1 H, t), 7.29 (3 H, m), 7.39 (1 H, m), 7.59 (2 H, d), 7.77 (1 H, s), 7.99 (1 H, d, J = 7, 9 Hz, H-6), 10.31 (1 H, s, OH), 11.55 (1 H, s, NH); MS (ESI) mass / charge = 482.6 [M + H] ⁺ ;

Compound 55 : ¹ H NMR (300 MHz, DMSO), δ (ppm): 2.76 (3 H, s, 9-Me), 3.46-3.53 (1 H, m, H- 10), 3.76-3.79 (1 H, m, H-10), 4.09-4.20 (2 H, m, 2 × H-2), 4.32-4.37 (1 H, m, H-1), 6.77-8.82 (3 H, m, H-3 ', H-2``), 7.21-7.33 (3 H, H-7, H -8, H-4 '), 7.51-7.59 (2 H, m, H-4, H-5'), 7.63-7.67 (3 H, m, H-7 ', H-1``), 8.02 (1 H, d, J = 8.4 Hz, H-6), 10.35 (1 H, s, OH), 11.59 (1 H, s, NH ); MS (ESI) mass / charge = 482.5 [M + H] ⁺ ;

Compound 56 : ¹ H NMR (300 MHz, DMSO-D ₆ ), δ (ppm): 2.73 (3 H, s, 9-Me), 3.73 (2 H, m), 4, 04 (1 H, m), 4.14 (1 H, t), 4.34 (1 H, t), 6.73 (1 H, m), 6.87 (1 H, s), 7, 23 (6 H, m), 7.37 (1 H, d, J = 8.22 Hz), 7.46 (2 H, d, J = 8.37 Hz), 7.86 (1 H, s ), 7.99 (1 H, d, J = 8.1 Hz, H-6), 10.33 (1 H, s, OH), 11.76 (1 H, s, NH); MS (ESI) mass / charge = 482.6 [M + H] ⁺ ;

Compound 57 : ¹ H NMR (300 MHz, DMSO), δ (ppm): 2.76 (3 H, s, 9-Me), 3.47-3.53 (1 H, m, H- 10), 3.77-3.81 (1 H, m, H-10), 4.10 (1 H, d, J = 10.8 Hz, H-2), 4.18 (1 H, t , J = 7.5 Hz, H-2), 4.31-4.35 (1 H, m, H-1), 6.75 (1 H, m, H-4``), 6.87 (1 H, s, H-3 '), 7.19-7.33 (5 H, m, H-7, H-8, H-5', H-2``, H-3 '') 7.51-7.68 (3 H, m, H-4, H-4 ', H-6'), 8.02 (1 H, d, J = 7.5 Hz, H-6), 10.36 (1 H, s, OH); 11.76 (1 H, s, NH); MS (ESI) mass / charge = 482.6 [M + H] ⁺ ;

Compound 103 : ¹ H NMR (300 MHz, DMSO-d ₆ ), δ (ppm): 2.75 (3 H, s, 9-Me), 3.49 (1 H, m, H-10 ), 3.75 (1 H, m, H-10), 3.82 (3 H, s, MeO), 4.08 (1 H, d, J = 10.9 Hz, H-2), 4 , 16 (1 H, m, H-2), 4.35 (1 H, m, H-1), 6.89 (1 H, s, H-3 '), 7.06 (2 H, d , J = 8.6 Hz, H-3``), 7.21 (1 H, t, J = 7.6 Hz, H-7), 7.31 (1 H, d, J = 6.8 Hz, H-8), 7.37 (1 H, d, J = 8.4 Hz, H-6 '), 7.47 (1 H, d, J = 8.4 Hz, H-7') 7.55 (1 H, br.s., H-4), 7.83 (2 H, d, J = 8.6 Hz, H-3``), 8.02 (1 H, d, J = 7.7 Hz, H-6), 10.34 (1 H, br s, OH), 11.73 (1 H, s, NH); MS (ESI) mass / charge = 497 [M + H] ⁺ .

Example 6

Compound 67 : ¹ H NMR (300 MHz, DMSO-d ₆ ), δ (ppm): 2.76 (3 H, s, 9-Me), 3.10 (6 H, s, NMe), 3.60 (1 H, t, J = 9.9 Hz, H-10), 3.77 (1 H, d, J = 10.3 Hz, H-10), 4.00 (1 H, broad s, H-1), 4.20 (1 H, t, J = 7.7 Hz, H-2), 4.32 (1 H, t, J = 8.2 Hz, H-2), 6.98 (2 H, d, J = 9.5 Hz, H-3``), 7.23 (1 H, t, J = 6.9 Hz, H-7), 7.34 (1 H , J = 6.9 Hz, H-8), 7.55 (1 H, br.s, H-4), 7.72 (1 H, d, J = 9.0 Hz, H-7 ') , 7.83 (1 H, d, J = 8.6 Hz, H-6 '), 7.96 (1 H, s, H-4'), 8.03 (1 H, d, J = 8 6 Hz, H-6), 8.14 (2 H, d, J = 9.0 Hz), 10.39 (1 H, s, NH); MS (ESI) mass / charge = 511 [M + H] ⁺ ;

Compound 68 : ¹ H NMR (300 MHz, DMSO-d ₆ ), δ (ppm): 2.15 (2 H, m, OCH ₂ C H ₂ ), 2.76 (3 H, s, 9 -Me), 2.84 (6 H, d, J = 4.8 Hz, NMe), 3.25 (2 H, m, NC H ₂ CH ₂ ), 3.55 (1 H, t, J = 11.0 Hz, H-10), 3.77 (1 H, d, J = 11.0 Hz, H-10), 4.04 (1 H, d, J = 11 Hz, H-2), 4.13-4.22 (3 H, m, H-1, OCH ₂ ), 4.34 (1H, m, H-2), 7.18 (2 H, d, J = 9.1 Hz, H-3``), 7.22 (1 H, t, J = 6.9 Hz, H-7), 7.33 (1 H, d, J = 6.6 Hz, H-8), 7 , 54 (1 H, dd, J = 8.5 Hz, J = 0.5 Hz, H-6 '), 7.60 (1H, br s, H-4), 7.72 (1 H, d, J = 8.1 Hz, H-7 '), 7.90 (1H, s, H-4'), 8.02 (1 H, d, J = 8.4 Hz, H-6), 8.19 (2 H, d, J = 9.3 Hz, H-2``), 9.45 (1 H, s, OH), 10.38 (1H, s, NH); MS (ESI) mass / charge = 569 [M + H] ⁺ ;

Compound 69 : ¹ H NMR (300 MHz, DMSO-d ₆ ), δ (ppm): 2.76 (3 H, s, 9-Me), 3.51 (5 H, m, 2 × O -CH ₂ , H-10 _a ), 3.78 (3 H, m, O-CH ₂ , H-10 _b ), 4.06 (1 H, d, J = 10.8 Hz, H-1) , 4.22 (3 H, m, O-CH ₂ , H-2 _a ), 4.33 (1 H, m, H-2 _b ), 4.63 (1 H, m, OH), 7, 10 (2 H, d, J = 8.9 Hz, 2 × CH), 7.21 (1 H, t, J = 8.2 Hz, H-7 '), 7.32 (1 H, d, J = 7.0 Hz, H-8 '), 7.44 (1 H, d, J = 8.9 Hz, CH), 7.57 (1 H, m, CH), 7.77 (1 H , s, H-4 '), 8.01 (1 H, d, J = 8.2 Hz, H-6'), 8.14 (2 H, d, J = 8.9 Hz, 2 × CH ), 10.40 (1 H, s, OH), 12.01 (1 H, broad s), 12.53 (1 H, broad s); MS (ESI) mass / charge = 615.6 [M + H] ⁺ ;

Compound 70 : ¹ H NMR (300 MHz, DMSO-d ₆ ), δ (ppm): 2.76 (3 H, s, 9-Me), 3.51-3.60 (5 H, m , 2 × OCH _2, H-10 _a ), 3.74-3.85 (3 H, m, OCH ₂ , H-10 _b ), 4.06 (1 H, m, H-1), 4, 14-4.25 (3 H, m, OCH ₂ , H-2 _a ), 4.35 (1 H, m, H-2 _b ), 4.65 (1 H, m, OH), 7.11 (1 H, d, J = 9.1 Hz, CH), 7.22 (1 H, t, J = 8.1 Hz, H-7 '), 7.33 (1 H, d, J = 7 , 1 Hz, H-8 '), 7.50 (3 H, m, 3 × CH), 7.65 (1 H, d, J = 8.1 Hz), 7.80 (3 H, m, 3 × CH), 8.00 (2 H, m, H-4 ', H-6'), 10.36 (1 H, s, OH), 13.18 (1 H, s, NH); MS (ESI) mass / charge = 572.5 [M + H] ⁺ ;

Compound 82 : ¹ H NMR (300 MHz, DMSO-d ₆ ), δ (ppm): 2.76 (3 H, s, 9-Me), 3.35-3.65 (13 H, m 6 × CH ₂ O, H-10), 3.73-3.85 (3 H, m, H-10, CH ₂ O), 4.06 (1 H, m, H-2), 4, 13-4.25 (3 H, m, H-2, CH ₂ O), 4.35 (1 H, m, H-1), 4.57 (1 H, t, J = 5.4 Hz, OH), 7.12 (1 H, d, J = 8.2 Hz, H-4``), 7.22 (1 H, t, J = 7.7 Hz, H-7), 7.32 (1 H, d, J = 6.8 Hz, H-8), 7.40-8.00 (7 H, m, H-4, H-4 ', H-5', H-6 ', H-2``, H-5 '', H-6``), 8.02 (1 H, d, J = 7.9, H-6), 10.36 (1 H, s, OH) 12.17 (1 H, s, NH); MS (ESI) mass / charge = 660 [M + H] ⁺ ;

Compound 83 : ¹ H NMR (300 MHz, DMSO-d ₆ ), δ (ppm): 2.76 (3 H, s, 9-Me), 3.37-3.65 (13 H, m 6 × CH ₂ O, H-10), 3.73-3.83 (3 H, m, H-10, CH ₂ O), 4.07 (1 H, m, H-2), 4, 12-4.26 (3 H, m, H-2, CH ₂ O), 4.35 (1 H, m, H-1), 4.57 (1 H, t, J = 5.4 Hz, OH), 7.15 (2 H, d, J = 8.8 Hz, H-3``), 7.22 (1 H, t, J = 7.7 Hz, H-7), 7.32 (1 H, d, J = 6.9 Hz, H-8), 7.47 (1 H, m, H-6 'tautomers), 7.60 (1 H, broad s, H-4), 7.61 + 7.72 (1 H, d, J = 8.3, H-7 'tautomers), 7.76 + 7.93 (1 H, s, H-4' tautomers), 8.02 ( 1 H, d, J = 8.4, H-6), 10.36 (1 H, s, OH), 13.03 (1 H, s, NH); MS (ESI) mass / charge = 660 [M + H] ⁺ ;

Compound 88 : ¹ H NMR (300 MHz, DMSO-d ₆ ), δ (ppm): 2.76 (3 H, s, 9-Me), 3.49 (1 H, m, H-10 ), 3.78 (1 H, d, J = 10.1 Hz, H-10), 4.03 (1 H, m, H-2), 4.20 (1 H, m, H-2) , 4.34 (1 H, m, H-1), 6.71 (2 H, d, J = 8.6 Hz, H-3``), 7.23 (1 H, t, J = 7.5 Hz, H-7), 7.33 (1 H, d, J = 6.9 Hz, H-8), 7.50-7.75 (3 H, m, H-4, H- 7 ', H-5``), 7.80-7.98 (5 H, m, H-6', H-4 '', H-6``, H2 '''), 8.00- 8.07 (2 H, m, H-6, H-4 '), 8.83 (1 H, s, H-2``), 10.16 (1 H, s, OH), 10.40 (1 H, broad s, NH); MS (ESI) mass / charge = 602 [M + H] ⁺ ;

Compound 89 : ¹ H NMR (300 MHz, DMSO-d ₆ ), δ (ppm): 2.76 (3 H, s, 9-Me), 3.56 (1 H, m, H-10 ), 3.78 (1 H, d, J = 9.2 Hz, H-10), 4.07 (1 H, m, H-2), 4.18 (1 H, m, H-2) , 4.34 (1 H, m, H-1), 6.89 (2 H, d, J = 8.7 Hz, H-3``), 7.21 (1 H, t, J = 7.7 Hz, H-7), 7.32 (1 H, d, J = 6.8 Hz, H-8), 7.49 (1 H, m, H-6 '), 7.60 ( 1 H, broad s, H-4), 7.63 + 7.74 (1 H, d, J = 8.2 Hz, H-7 'tautomers), 7.79 + 7.95 (1 H, s, H-4 'tautomers), 7.89 (2 H, d, J = 8.7 Hz, H-2''), 7.98 (2 H, d, J = 8.8 Hz, H -3``), 8.02 (1 H, d, J = 8.2 Hz, H-6), 8.18 (2 H, d, J = 8.8 Hz, H-2 ''), 10.15 (1 H, s, OH); 10.24 (1 H, s, OH); 10.37 (1 H, br s, NH); MS (ESI) mass / charge = 603 (M + H ⁺ );

Compound 90 : ¹ H NMR (300 MHz, DMSO-d ₆ ), δ (ppm): 2.76 (3 H, s, 9-Me), 3.54 (1 H, m, H-10 ), 3.78 (1 H, d, J = 10.7 Hz, H-10), 3.86 (3 H, s, OMe), 4.07 (1 H, d, J = 11.0 Hz , H-2), 4.18 (1 H, m, H-2), 4.35 (1 H, m, H-1), 7.11 (1 H, d, J = 8.4 Hz, H-5``), 7.21 (1 H, dd, J = 6.7 Hz, 8.0 Hz, H-7), 7.32 (1 H, d, J = 6.7 Hz, H -8), 7.46 (1 H, d, J = 8.4 Hz, H-7 '), 7.57 (1 H, broad s, H-4), 7.60-7.70 ( 2 H, m, H-2``, H-6 ''), 7.74 (1 H, m, H-6 '), 7.91 (1 H, broad s, H-4'), 8.01 (1 H, d, J = 8.0 Hz, H-6), 9.33 (1 H, s, OH), 10.36 (1 H, s, OH), 12.96 (1 H, s, NH); MS (ESI) mass / charge = 514 [M + H] ⁺ ;

Compound 91 : ¹ H NMR (300 MHz, DMSO-d ₆ ), δ (ppm): 2.76 (3 H, s, 9-Me), 3.46 (4 H, broad s, 2 × CH ₂ O), 3.56 (1 H, m, H-10), 3.77 (1 H, m, H-10), 3.88 (2 H, t, J = 5.2 Hz, CH ₂ O), 4.08 (1 H, m, H-2), 4.20 (1 H, m, H-2), 4.35 (1 H, m, H-1), 4.64 (3 H, m, CH ₂ O, OH), 7.21 (1 H, t, J = 7.7 Hz, H-7), 7.33 (1 H, d, J = 6.7 Hz, H-8), 7.49 (1 H, m, H-7 '), 7.60 (1 H, broad s, H-4), 7.62 + 7.74 (1 H, d, J = 7.9 Hz, H-6 'tautomers), 7.79 + 7.96 (1 H, s, H-4' tautomers), 8.02 (1 H, d, J = 8.0 Hz, H -6), 8.05 (2 H, d, J = 8.8, H-2``), 8.18 (2 H, d, J = 8.8, H-3 ''), 8, 75 (1 H, s, triazole-H), 10.36 (1 H, s, NH), 10.70 (1 H, s, OH), 13.11 (1 H, broad s, NH); MS (ESI) mass / charge = 666 [M + H] ⁺ ;

Compound 92 : ¹ H NMR (300 MHz, DMSO-d ₆ ), δ (ppm): 2.76 (3 H, s, 9-Me), 3.55 (1 H, m, H-10 ), 3.78 (1 H, m, H-10), 3.86 (3 H, s, OMe), 4.07 (1 H, m, H-2), 4.18 (1 H, m , H-2), 4.35 (1 H, m, H-1), 7.14 (2 H, d, J = 8.8 Hz, H-3``), 7.21 (1 H, dd, J = 6.9 Hz, 8.2 Hz, H-7), 7.31 (1 H, d, J = 6.9 Hz, H-8), 7.46 + 7.48 (1 H d, J = 8.2 Hz, H-6 ', tautomers), 7.56 (1 H, broad s, H-4), 7.61 + 7.73 (1 H, d, J = 8 , 2, H-7 ', tautomers), 7.76 + 7.93 (1 H, s, H-4' tautomers), 8.02 (1 H, d, J = 8.2 Hz, H-6 ), 8.16 (2 H, d, J = 8.8 Hz, H-2``), 10.36 (1 H, br s, OH), 13.02 (1 H, s, NH) ; MS (ESI) mass / charge = 498 (M + H ⁺ );

Compound 93 : ¹ H NMR (300 MHz, DMSO-d ₆ ), δ (ppm): 2.76 (3 H, s, 9-Me), 3.48 (1 H, m, H-10 ), 3.78 (1 H, d, J = 10.6 Hz, H-10), 4.01 (1 H, m, H-2), 4.21 (1 H, m, H-2) , 4.33 (1 H, m, H-1), 6.68 (2 H, d, J = 8.6 Hz, H-3``), 7.23 (1 H, t, J = 7.7 Hz, H-7), 7.33 (1 H, d, J = 6.7 Hz, H-8), 7.74 (1 H, d, J = 8.3 Hz, H-7 '), 7.70 (1 H, br s, H-4), 7.79 (2 H, d, J = 8.6 Hz, H-2''), 7.89 (1 H, d, J = 8.3 Hz, H-6 '), 8.02 (1 H, d, J = 7.0 Hz, H-6), 8.04 (1 H, s, H-4') 8.10 (2 H, d, J = 8.9 Hz, H-3``), 8.26 (2 H, d, J = 8.9 Hz, H-2 ''), 10.25 (1 H, s, OH), 10.41 (1 H, br s, NH); MS (ESI) mass / charge = 602 [M + H] ⁺ ;

Compound 94 : ¹ H NMR (300 MHz, DMSO-d ₆ ), δ (ppm): 2.76 (3 H, s, 9-Me), 3.52 (4 H, broad s, 2 × CH ₂ O), 3.56 (1 H, m, H-10), 3.70-3.81 (3 H, m, H-10, CH ₂ O), 4.06 (1 H, d , J = 10.5 Hz, H-2), 4.13-4.23 (3 H, m, H-2, CH ₂ O), 4.35 (1 H, m, H-1), 4 60 (1 H, br s, OH), 7.15 (2 H, d, J = 8.8 Hz, H-3``), 7.22 (1 H, t, J = 8.2 Hz, H-7), 7.33 (1 H, d, J = 6.9 Hz, H-8), 7.47 (1 H, d, J = 8.4 Hz, H-2``) , 7.60 (1 H, broad s, H-4), 7.65 (1 H, broad s, H-7 '), 7.85 (1 H, broad s, H-4') 8.02 (1 H, d, J = 8.0 Hz, H-6), 8.15 (2 H, d, J = 8.8, H-3``), 10.36 (1 H , s, OH); MS (ESI) mass / charge = 572 [M + H] ⁺ ;

Compound 95 : ¹ H NMR (300 MHz, DMSO-d ₆ ), δ (ppm): 2.75 (3 H, s, 9-Me), 3.59 (1 H, m, H-10 ), 3.77 (1 H, d, J = 10.4 Hz, H-10), 4.02 (1 H, m, H-2), 4.20 (1 H, m, H-2) , 4.34 (1 H, m, H-1), 7.15 (1 H, d, J = 8.0 Hz, H-4``), 7.23 (1 H, t, J = 7 , 8 Hz, H-7), 7.33 (1 H, d, J = 7.0 Hz, H-8), 7.49 (1 H, t, J = 7.8 Hz, H-5 ''), 7.60-7.80 (4 H, m, H-4, H-7', H-2``, H-6 ''), 7.85 (1 H, d, J = 8 , 3 Hz, H-6 '), 8.01 (1 H, s, H-4'), 8.02 (1 H, d, J = 8.0 Hz, H-6), 10.42 ( 1 H, s, OH); MS (ESI) mass / charge = 483 [M + H] ⁺ ;

Compound 96 : ¹ H NMR (300 MHz, DMSO-d ₆ ), δ (ppm): 2.75 (3 H, s, 9-Me), 3.54 (1 H, m, H-10 ), 3.78 (1 H, d, J = 10.9 Hz, H-10), 3.90 (3 H, s, OMe), 4.07 (1 H, d, J = 10.7 Hz , H-2), 4.18 (1 H, m, H-2), 4.35 (1 H, m, H-1), 6.94 (1 H, d, J = 8.2 Hz, H-5``), 7.21 (1 H, d, J = 7.7 Hz, H-7), 7.32 (1 H, d, J = 6.7 Hz, H-8), 7 47 (1 H, d, J = 8.9 Hz, H-6 '), 7.55 (1 H, broad s, H-4), 7.60-7.70 (2 H, m, H-6``, H-7 '), 7.78 (1 H, s, H-2''), 7.84 (1 H, s, H-4'), 8.02 (1 H, d, J = 8.1 Hz, H-6), 9.61 (1 H, s, OH), 10.36 (1 H, s, OH), 12.97 (1 H, s, NH); MS (ESI) mass / charge = 514 [M + H] ⁺ ;

Compound 97 : ¹ H NMR (300 MHz, DMSO-d ₆ ), δ (ppm): 2.75 (3 H, s, 9-Me), 3.54 (1 H, m, H-10 ), 3.77 (1 H, d, J = 9.7 Hz, H-10), 4.06 (1 H, d, J = 10.9 Hz, H-2), 4.18 (1 H , m, H-2), 4.35 (1 H, m, H-1), 6.94 (2 H, d, J = 8.7 Hz, H-3``), 7.21 (1 H, t, J = 7.6 Hz, H-7), 7.31 (1 H, d, J = 6.7 Hz, H-8), 7.47 (1 H, d, J = 8, 2 Hz, H-6 '), 7.56 (1 H, br s, H-4), 7.65 (1 H, d, J = 8.2, H-7'), 7.83 ( 1 H, s, H-4 '), 8.01 (1 H, d, J = 7.9 Hz, H-6), 8.04 (2 H, d, J = 8.7 Hz, H- 2``), 10.05 (1 H, s, OH), 10.36 (1 H, s, OH), 13.06 (1 H, br s, NH); MS (ESI) mass / charge = 484 [M + H] ⁺ .

Example 7

Compound 33 : ¹ H NMR (400 MHz, DMSO-d ₆ ), δ (ppm): 2.75 (3 H, s, 9-Me), 3.06-3.13 (1 H, m , H-10), 3.78 (1 H, d, J = 11.5 Hz, H-10), 4.04 (1 H, m, H-1), 4.19 (1 H, t, J = 8.2 Hz, H-2), 4.33 (1 H, t, J = 9.3 Hz, H-2), 7.00 (2 H, broad s, Ph-H), 7 23 (1 H, t, J = 7.5 Hz, H-7), 7.33 (1H, d, J = 7.0 Hz, H-8), 7.60-8.50 (8 H , m), 10.38 (1 H, s, OH), 10.91 (1 H, s, NH); MS (ESI) mass / charge = 526 [M + H] ⁺ .

Example 8

Compound 34 : ¹ H NMR (300 MHz, DMSO), δ (ppm): 2.76 (3 H, s, 9-Me), 3.50 (1 H, t, J = 9.3 Hz , H-10), 3.78 (1 H, d, J = 13.5 Hz, H-10), 4.06 (1 H, d, J = 11.7 Hz, H-2), 4, 15-4.22 (1 H, m, H-2), 4.29-4.36 (1 H, m, H-1), 5.96 (2 H, s, NH ₂ ), 6.61 (2 H, d, J = 9.0 Hz, H-2``), 7.21 (1 H, t, J = 7.2 Hz, H-7), 7.33 (1 H, d, J = 7.2 Hz, H-8), 7.38-7.78 (4 H, m, H-4, H-4 ', H-6', H-7 '), 7.90 (2 H, d, J = 9.0 Hz, H-1``), 8.02 (1 H, d, J = 9.6 Hz, H-6), 10.35 (1 H, s, OH) 11.58 (1 H, s, NH); 12.45 (1 H, s, NH); MS (ESI) mass / charge = 526.2 [M + H] ⁺ ;

Compound 35 : ¹ H NMR (300 MHz, DMSO), δ (ppm): 2.75 (3 H, s, 9-Me), 3.33 (3 H, s, OMe), 3.45 -3.55 (1 H, m, H-10), 3.77 (1 H, m, H-10), 4.04 (1 H, m, H-2), 4.17-4.21 (1 H, m, H-2), 4.29-4.36 (1 H, m, H-1), 7.06-7.51 (6 H, m, H-4, H-7, H-8, H-4 ', H-6', H-7 '), 8.01 (1H, m, H-6), 10.34-10.36 (1 H, m, OH), 11 05-11.14 (1 H, m, NH); MS (ESI) mass / charge = 422.1 [M + H] ⁺ .

Example 9

Compound 87 : ¹ H NMR (300 MHz, DMSO-d ₆ ), δ (ppm): 2.76 (3 H, s, 9-Me), 3.49 (1 H, m, H-10 ), 3.74 (1 H, m, H-10), 3.96 (1 H, m, H-2), 4.09 (3 H, s, N-Me), 4.19 (1 H , m, H-2), 4.34 (1 H, m, H-1), 6.67 (2 H, d, J = 8.6 Hz, H-3 ''), 7.24 ( 1 H, t, J = 7.6 Hz, H-7), 7.32 (1 H, d, J = 6.9 Hz, H-8), 7.70 (1 H, broad s, H -4), 7.79 (2 H, d, J = 8.6 Hz, H-2 ''), 7.84 (1 H, d, J = 8.8 Hz, H-7 '), 7.96 (2 H, d, J = 8.8 Hz, H-3``), 8.04 (1 H, d, J = 8.1 Hz, H-6), 8.06-8, 10 (2 H, m, H-6 ', H-7'), 8.13 (2 H, d, J = 8.8 Hz, H-2``), 10.23 (1 H, s, OH) 10.44 (1 H, s, NH); MS (ESI) mass / charge = 616 [M + H] ⁺ .

Example 10

Compound 71 : ¹ H NMR (300 MHz, DMSO-d ₆ ), δ (ppm): 2.79 (3 H, s, 9-Me), 3.52 (1 H, m, H-10 _a ), 3.80 (1 H, m, H-10 _b ), 4.31 (1 H, m, H-2 _a ), 4.49 (1 H, m, H-1), 4.65 (1 H, m, H-2 _b ), 6.89 (2 H, d, J = 8.4 Hz, 2 × CH), 7.16 (1 H, s, CH), 7.25 (1 H, t, J = 7.5 Hz, H-7 '), 7.35 (1 H, m, H-8'), 7.90 (3 H, m, 2 × CH, H-4 ') 8.05 (1 H, d, J = 8.4 Hz, H-6 '), 8.50 (1 H, m, CH), 8.63 (1 H, m, CH), 10.10 (1 H, s, OH), 10.14 (1 H, s, NH), 10.47 (1 H, s, OH), 12.24 (1 H, s, NH);

Compound 72 : ¹ H NMR (300 MHz, DMSO), δ (ppm): 2.79 (3 H, s, 9-Me), 3.39-3.78 (17 H, m, H- 10, H-10, OH), 4.21 (2 H, t, J = 5.1 Hz, OCH ₂ ), 4.31 (1 H, t, J = 11.4 Hz, H-2), 4.48 (1 H, d, J = 11.1 Hz, H-2), 4.66 (1 H, m, H-1), 7.10 (2 H, d, J = 9.0 Hz , H-2 ''), 7.16 (1 H, s, H-3 '), 7.25 (1 H, t, J = 6.9 Hz, H-7), 7.34 (1 H d, J = 6.6 Hz, H-8), 7.90-8.06 (4 H, m, H-4, H-6, H-1``), 8.53 (1 H, s, H-4 '), 8.65 (1 H, s, H-6'), 10.26 (1 H, s, NH), 10.47 (1 H, s, OH), 12.27 (1 H, s, NH); MS (ESI) mass / charge = 703.5 [M + H] ⁺ ;

Compound 73 : ¹ H NMR (300 MHz, DMSO-d ₆ ), δ (ppm): 2.79 (3 H, s, 9-Me), 3.22 (3 H, s, OMe), 3.39-3.65 (13 H, m, 6 × CH ₂ , H-10 _a ), 3.81 (3 H, m, OCH ₂ , H-10 _b ), 4.20 (2 H, m , OCH ₂ ), 4.31 (1 H, m, H-2 _a ), 4.49 (1 H, d, J = 10.8 Hz, H-1), 4.66 (1 H, m, H-2 _b ), 6.92 (1 H, d, J = 8.3 Hz, CH), 7.16 (1 H, d, J = 2.2 Hz, CH), 7.24 (1 H , t, J = 6.9 Hz, H-7 '), 7.35 (1 H, m, H-8'), 7.55 (1 H, d, J = 8.3 Hz, CH), 7.61 (1 H, m, CH), 7.91 (1 H, s, H-4 '), 8.05 (1 H, d, J = 7.5 Hz, H-6'), 8 44 (1 H, d, J = 2.2 Hz, CH), 8.62 (1 H, d, J = 2.2 Hz, CH), 9.69 (1 H, s, NH), 10 12 (1 H, s, OH); 10.47 (1 H, s, OH); 12.25 (1 H, s, NH); MS (ESI) mass / charge = 733.5 [M + H] ⁺ ;

Compound 74 : ¹ H NMR (300 MHz, DMSO-d ₆ ), δ (ppm): 2.79 (3 H, s, 9-Me), 3.24 (3 H, s, OMe), 3.40-3.64 (13 H, m, 6 × CH ₂ , H-10 _a ), 3.79 (3 H, m, OCH ₂ , H-10 _b ), 4.19 (2 H, m , OCH ₂ ), 4.31 (1 H, m, H-2 _a ), 4.49 (1 H, d, J = 10.9 Hz, H-1), 4.66 (1 H, m, H-2 _b ), 7.07 (1 H, d, J = 8.2 Hz, CH), 7.16 (1 H, m, CH), 7.25 (1 H, t, J = 7, 2 Hz, H-7 '), 7.35 (1 H, d, J = 7.0 Hz, H-8'), 7.50 (2 H, m, CH), 7.93 (1 H, broad s, H-4 '), 8.05 (1 H, d, J = 8.2 Hz, H-6'), 8.51 (1 H, d, J = 2.3 Hz, CH) , 8.63 (1 H, d, J = 2.3 Hz, CH), 9.28 (1 H, s, NH), 10.18 (1 H, s, OH), 10.47 (1 H , s, OH), 12.24 (1 H, s, NH); MS (ESI) mass / charge = 733.5 [M + H] ⁺ ;

Compound 75 : ¹ H NMR (300 MHz, DMSO-d ₆ ), δ (ppm): 2.79 (3 H, s, 9-Me), 3.53 (5 H, m, 2 × OCH ₂ , H-10 _a ), 3.79 (3 H, m, OCH ₂ , H-10 _b ), 4.21 (2 H, m, OCH ₂ ), 4.31 (1 H, m, H- 2 _a ), 4.49 (1 H, d, J = 10.6 Hz, H-1), 4.63 (2 H, m, OH, H-2 _b ), 7.18 (1 H, s , CH), 7.20 (1 H, m, CH), 7.25 (1 H, t, J = 7.2 Hz, H-7 '), 7.35 (1 H, d, J = 6 , 9 Hz, H-8 '), 7.47 (1 H, t, J = 8.1 Hz, CH), 7.59 (2 H, m, 2 × CH), 7.94 (1 H, s, H-4 '), 8.05 (1 H, d, J = 8.1 Hz, H-6'), 8.54 (1 H, d, J = 2.4 Hz, CH), 8 66 (1 H, d, J = 2.4 Hz, CH), 10.37 (1 H, s, NH), 10.47 (1 H, s, OH), 12.28 (1 H, s , NH); MS (ESI) mass / charge = 615.5 [M + H] ⁺ ;

Compound 76 : ¹ H NMR (300 MHz, DMSO-d ₆ ), δ (ppm): 2.79 (3 H, s, 9-Me), 3.51 (1 H, t, J = 10 , 7 Hz, H-10), 3.80 (1 H, d, J = 11.3 Hz, H-10), 4.31 (1 H, t, J = 8.7 Hz, H-1) 4.49 (1 H, d, J = 10.5 Hz, H-2), 4.66 (1 H, dd, J = 10.5 Hz, 10.0 Hz, H-2), 5, 76 (2 H, s, NH ₂ ), 6.62 (2 H, d, J = 8.7 Hz, H-3 ''), 7.15 (1 H, d, J = 2.18 Hz, H-3 '), 7.25 (1 H, dd, J = 8.7 Hz, 7.0 Hz, H-7), 7.35 (1 H, d, J = 7.0 Hz, H- 8), 7.77 (2 H, d, J = 8.6 Hz, H-2``), 7.93 (1 H, s, H-4), 8.04 (1 H, d, J = 8.2 Hz, H-6), 8.50 (1 H, d, J = 2.2 Hz, H-4 '), 8.63 (1 H, d, J = 2.4 Hz, H -6 '), 9.92 (1 H, s, OH), 10.47 (1 H, s, NH), 12.20 (1 H, s, NH); MS (ESI) mass / charge = 526 [M + H] ⁺ ;

Compound 77 : ¹ H NMR (300 MHz, DMSO-d ₆ ), δ (ppm): 2.79 (3 H, s, 9-Me), 3.47-3.58 (5 H, m , CH ₂ , H-10), 3.75-3.85 (3 H, m, CH ₂ , H-10), 4.20 (2 H, m, CH ₂ ), 4.31 (1 H, t, J = 7.5 Hz, H-1), 4.49 (1 H, d, J = 10.9 Hz, H-2), 4.60-4.71 (2 H, m, H- 2, OH), 7.10 (2 H, d, J = 9.5 Hz, H-3 ''), 7.17 (1 H, d, J = 2.0 Hz, H-3 '), 7.25 (1 H, dd, J = 7.1 Hz, 8.5 Hz, H-7), 7.35 (1 H, d, J = 7.1 Hz, H-8), 7.94 (1 H, s, H-4), 8.00 (2 H, d, J = 8.9 Hz, H-2``), 8.05 (1 H, d, J = 8.3 Hz, H-6), 8.53 (1 H, d, J = 2.3 Hz, H-4 '), 8.65 (1 H, d, J = 2.4 Hz, H-6'), 10 25 (1 H, s, NH); 10.47 (1 H, s, OH); 12.26 (1 H, s, NH); MS (ESI) mass / charge = 615 [M + H] ⁺ .

Example 11

Compound 47 : ¹ H NMR (400 MHz, DMSO-d ₆ ), δ (ppm): 2.79 (3 H, s, 9-Me), 3.44-3.55 (5 H, m , H-10, 2 × OCH ₂ ), 3.79 (1 H, d, J = 11.5 Hz, H-10), 3.89 (2 H, t, J = 5.0 Hz, OCH ₂ ), 4.31 (1 H, t, J = 8.9 Hz, H-1), 4.48 (1 H, d, J = 10.6 Hz, H-2), 4.62-4, 69 (4 H, m, H-2, OH, OCH ₂ ), 7.17 (1 H, d, J = 2 Hz, H-3 '), 7.25 (1 H, dd, J = 7, 0 Hz, 8.3 Hz, H-7), 7.35 (1H, d, J = 7.0 Hz, H-8), 7.93 (1 H, s, H-4), 8.05 (1 H, d, J = 8.3 Hz, H-6), 8.56 (1 H, d, J = 2 Hz, H-4 '), 8.72-8.73 (2 H, m , H-6 ', triazole-H), 10.47 (1 H, s, OH), 10.64 (1 H, s, NH), 12.28 (1 H, s, NH); MS (ESI) mass / charge = 590 [M + H] ⁺ .

Example 12

Compound 58 : ¹ H NMR (300 MHz, DMSO), δ (ppm): 2.79 (3 H, s, 9-Me), 3.60 (1 H, m, H-10), 3 80 (1 H, m, H-10), 4.36 (1 H, m, H-2), 4.47 (1 H, m, H-2), 4.68 (1 H, m, H-1), 6.68 (2 H, d, J = 8.7 Hz, H-2``), 7.26 (1 H, t, J = 6.9 Hz, H-7), 7 , 37 (1 H, d, J = 6.6 Hz, H-8), 7.47 (1 H, s, H-3 '), 7.90 (2 H, d, J = 8.7 Hz , H-1 ''), 7.95-8.10 (2 H, m, H-4, H-6), 8.25 (1 H, s, H-4 '), 8.90 (1 H, s, H-7 '), 10.56 (1 H, s, OH), 11.25 (1 H, s, NH), 12.99 (1 H, s, NH); MS (ESI) mass / charge = 526.3 [M + H] ⁺ ;

Compound 59 : ¹ H NMR (300 MHz, DMSO), δ (ppm): 2.79 (3 H, s, 9-Me), 3.58 (1 H, m, H-10), 3 79 (1 H, m, H-10), 4.34 (1 H, m, H-2), 4.47 (1 H, m, H-2), 4.67 (1 H, m, H-1), 6.93 (2 H, d, J = 8.7 Hz, H-2``), 7.27 (1 H, t, J = 7.2 Hz, H-7), 7 , 35-7.42 (1 H, m, H-8, H-3 '), 7.98-8.08 (4 H, m, H-4, H-6, H-1''), 8.41 (1 H, s, H-4 '), 8.86 (1 H, s, H-7'), 10.16 (1 H, s, OH), 10.56 (1 H, s , OH), 11.15 (1 H, s, NH); 12.80 (1 H, s, NH); MS (ESI) mass / charge = 527.4 [M + H] ⁺ ;

Compound 60 : ¹ H NMR (300 MHz, DMSO), δ (ppm): 2.80 (3 H, s, 9-Me), 3.39-3.62 (14 H, m, H- 10, OH), 3.77 (3 H, m, H-10), 4.23 (2 H, t, J = 4.2 Hz), 4.36 (1 H, t, J = 6.9 Hz, H-2), 4.49 (1 H, d, J = 10.8 Hz, H-2), 4.70 (1 H, m, H-1), 7.12 (2 H, d , J = 8.7 Hz, H-2``), 7.27 (1 H, t, J = 7.2 Hz, H-7), 7.35-7.42 (2 H, m, H -8, H-3 '), 7.97-8.13 (4 H, m, H-4, H-6, H-1''), 8.38 (1 H, s, H-4' ), 8.86 (1 H, s, H-7 '), 10.54 (1 H, s, OH), 11.20 (1 H, s, NH), 12.78 (1 H, s, NH); MS (ESI) mass / charge = 703.5 [M + H] ⁺ ;

Compound 61 : ¹ H NMR (300 MHz, DMSO), δ (ppm): 2.79 (3 H, s, 9-Me), 3.24 (3 H, s, OMe), 3.40 -3.62 (13 H, m, H-10), 3.76-3.82 (3 H, m, H-10), 4.19 (2 H, t, J = 4.5 Hz), 4.34 (1 H, t, J = 7.5 Hz, H-2), 4.53 (1 H, d, J = 12.0 Hz, H-2), 4.70 (1 H, m , H-1), 7.06 (2 H, d, J = 8.7 Hz, H-2``), 7.23-7.28 (2 H, H-7, H-3 '), 7.35 (1 H, d, J = 6.9 Hz, H-8), 7.97-8.07 (4 H, m, H-4, H-6, H-1``), 8 45 (1 H, s, H-4 '), 8.68 (1 H, s, H-7'), 10.41 (1 H, s, NH), 10.59 (1 H, s, OH), 12.17 (1 H, s, NH); MS (ESI) mass / charge = 717.7 [M + H] ⁺ .

Example 13

Compound 81:^oneH NMR (300 MHz, DMSO-d₆), δ (ppm): 2.79 (3 H, s, 9-Me), 3.23 (3 H, s, OMe), 3.38-3.64 (13 H, m, 6 × OCH₂H-10_a), 3.78 (3 H, m, OCH₂H-10_b), 4.12 (2 H, m, OCH₂), 4.30 (1 H, m, H-2_a), 4.58 (1 H, m, H-1), 5.06 (1 H, d,J= 11.9 Hz, H-2_b), 6.92 (1-H, dd,J= 2.3 Hz, 9.1 Hz, CH), 7.18 (1 H, s, CH), 7.23 (1 H, t,J =7.2 Hz, H-7 '), 7.36 (3 H, m, 2 × CH, H-8'), 7.62 (1 H, dd,J =2.0 Hz 9.9 Hz, CH), 7.76 (1 H, d,J =9.7 Hz, CH), 8.05 (1 H, d,J =7.9 Hz, H-6`), 8.10 (1 H, br s, H-4 '), 8.70 (1 H, s, CH), 9.42 (1 H, s, CH ), 10.37 (1 H, s, OH), 10.42 (1 H, s, NH), 11.64 (1 H, s, NH); MS (ESI)mass / charge= 756.5 [M + H]⁺;

Compound 84 : ¹ H NMR (300 MHz, DMSO-d ₆ ), δ (ppm): 2.78 (3 H, s, 9-Me), 3.37-3.65 (13 H, m 6 × CH ₂ O, H-10), 3.71-3.81 (3 H, m, CH ₂ O, H-10), 4.20 (1 H, t, J = 4.5 Hz, CH ₂ O), 4.30 (1 H, t, J = 8.2 Hz, H-1), 4.52-4.62 (2 H, m, H-2, OH), 5.05 ( 1 H, d, J = 11.8 Hz, H-2), 7.12 (2 H, d, J = 8.8 Hz, H-3``), 7.23 (1 H, t, J = 7.7 Hz, H-7), 7.33 (1 H, d, J = 6.7 Hz, H-8), 7.57 (1 H, dd, J = 1.8 Hz, 9, 7 Hz, H-6 '), 7.73 (1 H, d, J = 9.7 Hz, H-7'), 8.00 (2 H, d, J = 8.8 Hz, H-2 ''), 8.04 (1 H, d, J = 8.4 Hz, H-6), 8.09 (1 H, br s, H-4), 8.66 (1 H, s, H-3 '), 9.46 (1 H, s, H-4'), 10.28 (1 H, s, NH), 10.42 (1 H, s, OH); MS (ESI) mass / charge = 703 [M + H] ⁺ ;

Compound 85 : ¹ H NMR (300 MHz, DMSO-d ₆ ), δ (ppm): 2.78 (3 H, s, 9-Me), 3.42 (1 H, t, J = 10 5 Hz, H-10), 3.75 (1 H, d, J = 11.0 Hz, H-10), 4.30 (1 H, t, J = 8.9 Hz, H-1) 4.57 (1 H, dd, J = 7.6 Hz, 11.8 Hz, H-2), 5.04 (1 H, d, J = 11.8 Hz, H-2), 6, 89 (1 H, d, J = 8.7 Hz, H-3``), 7.23 (1 H, t, J = 7.6 Hz, H-7), 7.33 (1 H, d , J = 6.8 Hz, H-8), 7.57 (1 H, dd, J = 1.8 Hz, 9.7 Hz, H-6 '), 7.71 (1 H, d, J = 9.7 Hz, H-7 '), 7.90 (2 H, d, J = 8.7 Hz, H-2``), 8.04 (1 H, d, J = 8.1 Hz , H-6), 8.09 (1 H, br s, H-4), 8.66 (1 H, s, H-3 '), 9.44 (1 H, s, H-4' ), 10.17 (1 H, s, OH), 10.18 (1 H, s, NH), 10.42 (1 H, s, OH); MS (ESI) mass / charge = 527 [M + H] ⁺ ;

Compound 86 : ¹ H NMR (300 MHz, DMSO-d ₆ ), δ (ppm): 2.78 (3 H, s, 9-Me), 3.44 (1 H, t, J = 10 6 Hz, H-10), 3.76 (1 H, d, J = 10.3 Hz, H-10), 4.32 (1 H, t, J = 7.4 Hz, H-1) 4.58 (1 H, dd, J = 7.4 Hz, 11.2 Hz, H-2), 4.96 (1 H, d, J = 11.2 Hz, H-2), 5, 93 (1 H, br s, NH ₂ ), 6.63 (2 H, d, J = 8.4 Hz, H-3``), 7.24 (1 H, t, J = 7.6 Hz, H-7), 7.33 (1 H, d, J = 6.7 Hz, H-8), 7.73 (2 H, m, H-6 ', H-7'), 8, 04 (1 H, d, J = 8.2 Hz, H-6), 8.08 (1 H, broad s, H-4), 8.74 (1 H, s, H-3 '), 9.51 (1 H, s, H-4 '), 10.05 (1 H, s, NH), 10.45 (1 H, s, OH); MS (ESI) mass / charge = 526 [M + H] ⁺ .

Example 14

Compound 40 : ¹ H NMR (400 MHz, DMSO-d ₆ ), δ (ppm): 2.79 (3 H, s, 9-Me), 3.50 (1 H, m, H-10 ), 3.79 (1 H, d, J = 11.5 Hz, H-10), 4.36 (1 H, t, J = 8.9 Hz, H-1), 4.61 (1 H , t, J = 9.5 Hz, H-2), 4.92 (1 H, d, J = 11.5 Hz, H-2), 6.88 (2 H, d, J = 8.5 Hz, Ar-H), 7.25 (1 H, dd, J = 7.0 Hz, 8.5 Hz, H-7), 7.35 (1H, d, J = 7.0 Hz, H- 8), 7.80 (2 H, d, J = 8.9 Hz, Ar-H), 7.95-8.14 (8 H, m, H-4, H-6, Ar-H, NH ₂ ), 9.40 (1 H, s, triazole-H), 10.14 (1 H, s, OH), 10.50 (1 H, s, NH); MS (ESI) mass / charge = 553 [M + H] ⁺ ;

Compound 41 : ¹ H NMR (400 MHz, DMSO-d ₆ ), δ (ppm): 2.79 (3 H, s, 9-Me), 3.50 (1 H, t, J = 9 8 Hz, H-10), 3.79 (1 H, d, J = 11.5 Hz, H-10), 4.36 (1 H, t, J = 8.9 Hz, H-1) 4.61 (1 H, t, J = 9.5 Hz, H-2), 4.92 (1 H, d, J = 11.0 Hz, H-2), 6.90 (2 H, d, J = 8.5 Hz, Ar-H), 7.25 (1 H, dd, J = 7.0 Hz, 8.5 Hz, H-7), 7.35 (1H, d, J = 7.0 Hz, H-8), 7.90 (2 H, d, J = 8.6 Hz, Ar-H), 7.98-8.14 (6 H, m, H-4, H- 6, Ar-H), 9.40 (1 H, s, triazole-H), 10.16 (1 H, s, NH), 10.29 (1 H, s, OH), 10.49 (1 H, s, OH); MS (ESI) mass / charge = 554 [M + H] ⁺ .

Example 15

Compound 62 : ¹ H NMR (300 MHz, DMSO-d ₆ ), δ (ppm): 2.76 (3 H, s, 9-Me), 3.58 (1 H, m, H-10 _a ), 3.80 (1 H, m, H-10 _b ), 4.34 (1 H, m, H-1), 4.44 (1 H, m, H-2 _a ), 4.54 (1 H, m, H-2 _b ), 6.62 (2 H, d, J = 8.9 Hz, 2 × CH), 7.25 (1 H, t, J = 7.6 Hz, H -7 '), 7.36 (1 H, m, H-8'), 7.46 (1 H, t, J = 8.4 Hz, CH), 7.74 (2 H, d, J = 8.4 Hz, 2 × CH), 7.92 (1 H, d, J = 8.4 Hz, CH), 7.99 (1 H, s, H-4 '), 8.04 (1 H d, J = 8.4 Hz, H-6 '), 8.15 (1 H, s, CH), 9.98 (1 H, s, NH), 10.53 (1 H, broad s , OH); MS (ESI) mass / charge = 510.1 [M + H] ⁺ ;

Compound 63 : ¹ H NMR (300 MHz, DMSO-d ₆ ), δ (ppm): 2.25 (6 H, s, Me ₂ N), 2.67 (2 H, t, J = 5 , 7 Hz, C H ₂ NMe ₂ ), 2.76 (3 H, s, 9-Me), 3.57 (1 H, t, J = 10.2 Hz, H-10 _a ), 3.81 (1 H, m, H-10 _b ), 4.13 (2 H, t, J = 5.7 Hz, OCH ₂ ), 4.33 (1 H, m, H-1), 4.43 ( 1 H, m, H-2 _a ), 4.53 (1 H, m, H-2 _b ), 7.16 (1 H, d, J = 8.3 Hz, CH), 7.25 (3 H, m, H-7 ', 2 × CH), 7.35 (1 H, m, H-8'), 7.43 (1 H, t, J = 7.9 Hz, CH), 7, 98 (1 H, s, H-4 '), 8.04 (1 H, d, J = 6.8 Hz, H-6'), 10.53 (1 H, s, OH); MS (ESI) mass / charge = 427.2 [M + H] ⁺ ;

Compound 64:^oneH NMR (300 MHz, DMSO-d₆), δ (ppm): 2.41 (3 H, s, CH₃CO), 2.76 (3 H, s, 9-Me), 3.51 (1 H, m, H-10_a), 3.79 (1 H, m, H-10_b), 4.33 (2 H, m, H-2_a, H-1), 4.49 (1 H, m, H-2_b), 7.23 (1 H, t,J= 8.2 Hz, H-7 '), 7.31-7.38 (2 H, m, CH, H-8'), 7.69 (1 H, m, CH), 7.98 (1 H, s, H-4 '), 8.02 (1 H, d,J= 8.2 Hz, H-6), 10.48 (1 H, s, OH), 12.46 (1 H, broad s, NH); MS (ESI)mass / charge= 407.1 [M + H]⁺.

Example 16

Compound 65 : ¹ H NMR (300 MHz, DMSO-d ₆ ), δ (ppm): 2.75 (3 H, s, 9-Me), 3.59 (1 H, m, H-10 _a ), 3.76 (1 H, m, H-10 _b ), 4.02 (1 H, m, H-1), 4.18 (1 H, m, H-2 _a ), 4.33 (1 H, m, H-2 _b ), 6.07 (2 H, br.s, NH ₂ ), 6.70 (2 H, d, J = 8.2 Hz, 2 × CH), 7, 18-7.35 (2 H, m, H-7 ', H-8'), 7.58 (1 H, d, J = 8.2 Hz, CH), 7.80 (1 H, d, J = 8.5 Hz, CH), 7.90 (2 H, d, J = 8.5 Hz, 2 × CH), 7.94 (1 H, s, H-4 '), 8.02 ( 1 H, d, J = 8.1 Hz, H-6 '), 10.39 (1 H, broad s, OH); MS (ESI) mass / charge = 484.4 [M + H] ⁺ ;

Compound 66 : ¹ H NMR (300 MHz, DMSO-d ₆ ), δ (ppm): 2.75 (3 H, s, 9-Me), 3.60 (1 H, m, H-10 _a ), 3.77 (1 H, m, H-10 _b ), 4.00 (1 H, m, H-1), 4.19 (1 H, m, H-2 _a ), 4.33 (1 H, m, H-2 _b ), 6.06 (2 H, br s, NH ₂ ), 6.71 (2 H, d, J = 8.6 Hz, 2 × CH), 7, 22 (1 H, t, J = 7.6 Hz, H-7 '), 7.32 (1 H, d, J = 6.6 Hz, H-8'), 7.39 (1 H, m , CH), 7.59 (1 H, m, CH), 7.80 (1 H, d, J = 8.2 Hz, CH), 7.90 (1 H, d, J = 8.6 Hz , 2 × CH), 7.95 (1 H, s, H-4 '), 8.02 (1 H, d, J = 8.2 Hz, H-6'), 10.40 (1 H, broad s, OH); MS (ESI) mass / charge = 484.2 [M + H] ⁺ .

Example 17

Compound 98 : ¹ H NMR (300 MHz, DMSO-d ₆ ), δ (ppm): 2.76 (3 H, s, 9-Me), 3.58 (1 H, m, H-10 ), 3.78 (1 H, d, J = 10.6 Hz, H-10), 4.01 (1 H, m, H-2), 4.21 (1 H, m, H-2) , 4.37 (1 H, m, H-1), 6.77 (2 H, d, J = 8.5 Hz, H-3``), 7.23 (1 H, t, J = 7.6 Hz, H-7), 7.33 (1 H, d, J = 6.8 Hz, H-8), 7.75-7.85 (3 H, m, H-4 ', H -2````), 7.98-8.08 (3 H, m, H-6, H-3 ''), 8.12 (2 H, d, J = 8.8, H-2 ''), 8.14 (1 H, d, J = 8.2, H-5'), 8.47 (1 H, s, H-7 '), 10.22 (1 H, s, OH) 10.42 (1 H, broad s, NH); MS (ESI) mass / charge = 618 [M + H] ⁺ ;

Compound 99 : ¹ H NMR (300 MHz, DMSO-d ₆ ), δ (ppm): 2.75 (3 H, s, 9-Me), 3.59 (1 H, m, H-10 ), 3.77 (1 H, d, J = 10.4 Hz, H-10), 4.01 (1 H, m, H-2), 4.21 (1 H, m, H-2) , 4.35 (1 H, m, H-1), 6.75 (2 H, d, J = 8.6 Hz, H-3``), 7.22 (1 H, t, J = 7 , 7 Hz, H-7), 7.33 (1 H, d, J = 6.7 Hz, H-8), 7.70 (1 H, broad s, H-4), 7.72 ( 1 H, d, J = 8.4 Hz, H-5 '), 7.84 (2 H, d, J = 8.6 Hz, H-2''), 7.90-8.10 (2 H, m, H-6, H-4 '), 8.37 (1 H, s, H-7'), 10.40 (1 H, s, OH); MS (ESI) mass / charge = 500 [M + H] ⁺ ;

Compound 100 : ¹ H NMR (300 MHz, DMSO-d ₆ ), δ (ppm): 2.76 (3 H, s, 9-Me), 3.69 (1 H, m, H-10 ), 3.78 (1 H, m, H-10), 4.03 (1 H, m, H-2), 4.19 (1 H, m, H-2), 4.37 (1 H , m, H-1), 6.68 (2 H, d, J = 8.7 Hz, H-3``), 7.23 (1 H, dd, J = 6.7 Hz, 8.0 Hz, H-7), 7.33 (1 H, d, J = 6.7 Hz, H-8), 7.60 (1 H, broad s, H-4), 7.72 (1 H dd, J = 1.3 Hz, 8.4 Hz, H-6 '), 7.84 (1 H, d, J = 8.4 Hz, H-7'), 7.94 (2 H, d, J = 8.7 Hz, H-6``), 8.02 (1 H, d, J = 8.0 Hz, H-2 ''), 8.34 (1 H, d, J = 1.3 Hz, H-6), 10.39 (1 H, br s, OH), 12.53 (1 H, s, NH); MS (ESI) mass / charge = 543 [M + H] ⁺ .

Example 18

Compound 78 : ¹ H NMR (300 MHz, DMSO-d ₆ ), δ (ppm): 2.79 (3 H, s, 9-Me), 3.50 (1 H, m, H-10 ), 3.76 (1 H, d, J = 10.4 Hz, H-10), 4.31-4.40 (2 H, m, H-1, H-2), 4.47-4 , 54 (1 H, m, H-2), 6.86 (2 H, d, J = 8.5 Hz, H-3 ''), 6.91 (1 H, s, H-3 ') , 7.18-7.27 (2 H, m, H-7, C H = CH), 7.33 (1 H, d, J = 6.6 Hz, H-8), 7.38 (1 H, d, J = 9.0 Hz, H-7 '), 7.50 (1 H, dd, J = 9.0 Hz, 1.8 Hz, H-6'), 7.67 (1 H d, J = 14.9 Hz, CH = C H ), 7.87 (2 H, d, J = 8.9 Hz, H-2``), 7.99-8.06 (2 H, m, H-4 ', H-6), 8.20 (1 H, br s, H-4), 9.89 (1 H, s, NH), 10.03 (1 H, s, OH ), 10.43 (1 H, s, OH); 11.61 (1 H, s, NH); MS (ESI) mass / charge = 552 [M + H] ⁺ ;

Compound 79 : ¹ H NMR (300 MHz, DMSO-d ₆ ), δ (ppm): 2.79 (3 H, s, 9-Me), 3.49 (1 H, t, J = 9 4 Hz, H-10), 3.76 (1 H, d, J = 10.6 Hz, H-10), 4.31-4.41 (2 H, m, H-1, H-2 ), 4.45-4.55 (1 H, m, H-2), 5.70 (2 H, br s, NH ₂ ), 6.61 (2 H, d, J = 8.8 Hz , H-3 ''), 6.89 (1 H, s, H-3 '), 7.17-7.27 (2 H, m, H-7, C H = CH), 7.30- 7.40 (2 H, m, H-8, H-7 '), 7.50 (1 H, dd, J = 8.9 Hz, 2.1 Hz, H-6'), 7.67 ( 1 H, d, J = 15.0 Hz, CH = C H ), 7.74 (2 H, d, J = 8.7 Hz, H-2``), 7.98-8.05 (2 H, m, H-6, H-4 '), 8.21 (1 H, br s, H-4), 9.66 (1 H, s, NH), 10.44 (1 H, s , OH), 11.59 (1 H, s, NH); MS (ESI) mass / charge = 551 [M + H] ⁺ ;

Compound 80 : ¹ H NMR (300 MHz, DMSO-d ₆ ), δ (ppm): 2.78 (3 H, s, 9-Me), 3.47 (1 H, m, H-10 _a ), 3.75 (1 H, d, J = 11.1 Hz, H-10 _b ), 3.83 (3 H, s, OMe), 4.34 (2 H, m, H-2 _a , H-1), 4.53 (1 H, m, H-2 _b ), 6.85 (1 H, d, J = 2.0 Hz, CH), 7.21 (1 H, t, J = 7.9 Hz, H-7 '), 7.31 (1 H, s, H-8'), 7.37 (1 H, d, J = 15.3 Hz, = CH- ), 7, 57 (1 H, d, J = 3.2 Hz, CH), 7.65 (1 H, d, J = 15.3 Hz, = CH- ), 8.03 (1 H, d, J = 7 , 9 Hz, H-6 '), 8.07 (1 H, d, J = 3.2 Hz, CH), 8.21 (1 H, broad s, H-4'), 10.43 ( 1 H, s, OH); 12.12 (1 H, s, NH); MS (ESI) mass / charge = 448.1 [M + H] ⁺ .

Example 19

Compound 101 : ¹ H NMR (300 MHz, DMSO-d ₆ ), δ (ppm): 2.81 (3 H, s, 9-Me), 3.58 (1 H, t, J = 10 , 9 Hz, H-10), 3.81 (1 H, d, J = 10.9 Hz, H-10), 4.43 (1 H, t, J = 7.3 Hz, H-1) , 4.71 (1 H, dd, J = 7,2 Hz, 12.1 Hz, H-2), 5.36 (1 H, d, J = 12,1 Hz, H-2), 6, 71 (2 H, d, J = 8.2 Hz, H-3 ''), 7.23 (1 H, t, J = 7.6 Hz, H-7), 7.33 (1 H, d, J = 6.7 Hz, H-8), 7.78 (2 H, d, J = 8.2 Hz, H-2``), 7.91 (2 H, d, J = 8 , 7 Hz, H-2``), 8.01 (2 H, d, J = 8.7 Hz, H-3 ''), 8.07 (1 H, d, J = 8.0 Hz, H-6), 8.14 (1 H, s, H-4), 8.42 (1 H, s, H-5'-thiazole), 9.97 (1 H, s, NH), 10, 53 (1 H, s, OH); MS (ESI) mass / charge = 569 [M + H] ⁺ .

Example 20

Compound 102 : ¹ H NMR (300 MHz, DMSO-d ₆ ), δ (ppm): 2.65-2.85 (2 H, m, thiophene-CH ₂ ), 2.76 (3 H, s, 9-Me), 3.47 (1 H, m, H-10), 3.58-3.65 (2 H, m, CH ₂ N), 3.72-3.84 (3 H, m, CH ₂ N, H-10), 4.27 (1 H, m, H-1), 4.38 (1 H, m, H-2), 4.50-4.70 (3 H, m, CH ₂ C = O, H-1), 4.97 (2 H, br. a, NH _2), 6.50 (2 H, m, H-2 '), 6.91 (1 H , m, H-3 ''), 7.23 (1 H, t, J = 7.6 Hz, H-7), 7.33 (1 H, d, J = 6.9 Hz, H-8 ), 7.58 (1 H, broad s, H-4), 7.87 (1 H, s, H-2 '), 8.03 (1 H, s, H-6), 10.42 (1 H, s, OH); MS (ESI) mass / charge = 546 [M + H] ⁺ .

Example 21

Compound 103 : ¹ H NMR (200 MHz, CDCl 3), δ (ppm): 2.34 (3 H, s, Me), 2.82 (3 H, s, 9-Me), 3.30 (1 H, t, J = 11.0 Hz), 3.68 (1 H, d, J = 11.3 Hz), 3.95 (3 H, s, Me), 4.12 (1 H, m, H-1), 4.43 (1 H, t, J = 6.90 Hz, H-2), 4.56 (1 H, d, J = 11.0 Hz, H-2), 6 46 (1 H, d, J = 16.1 Hz), 6.87 (1 H, d, J = 1.7 Hz), 7.11 (1 H, d, J = 1.7 Hz), 7.28 (1 H, m, H-7), 7.31 (1 H, s, H-8), 7.45 (1 H, d, J = 16.1 Hz), 7.66 (1 H, s, H-4), 8.15 (1 H, d, J = 8.9 Hz, H-6); MS (ESI) mass / charge = 423.1 [M + H] ⁺ ;

Compound 104 : ¹ H NMR (300 MHz, DMSO), δ (ppm): 2.26 (3 H, s, Me), 2.78 (3 H, s, 9-Me), 3.46 (1 H, t, J = 11.0 Hz), 3.78 (1 H, d, J = 11.7 Hz), 4.29 (1 H, t, J = 7.75 Hz, H-2 ), 4.44 (1 H, d, J = 10.7 Hz, H-2), 4.60 (1 H, m, H-1), 6.60 (1 H, d, J = 16, 1 Hz), 7.21 (1 H, d, J = 7.0 Hz, H-7), 7.25 (1 H, s), 7.33 (1 H, d, J = 6.9 Hz , H-8), 7.52 (1 H, d, J = 3.0 Hz, H-12), 7.60 (1 H, d, J = 16.3 Hz, H-14), 7, 98 (1 H, s, H-4), 8.02 (1 H, d, J = 8.5 Hz, H-6), 10.41 (1 H, s, NH); MS (ESI) mass / charge = 409.2 [M + H] ⁺ .

Example 22

Compound 105 : ¹ H NMR (400 MHz, DMSO), δ (ppm): 2.73 (3 H, s, 9-Me), 3.61 (1 H, m, H-10), 3 74 (1 H, d, J = 10.8 Hz, H-10), 4.24 (1 H, m), 4.45 (1 H, d), 4.61 (1 H, t), 6.62 (2 H, d), 7.15 (2 H, t), 7.18 (1 H, d), 7.43 (1 H, s), 7.57 (2 H, d), 7.70 (4 H, d), 7.94 (1 H, s), 7.98 (1 H, d), 9.73 (1 H, s, NH), 10.35 (1 H, s , OH), 11.77 (1 H, s, NH); MS (ESI) mass / charge = 551.3 [M + H] ⁺ .

Example 23

In vitro IC _fifty analysis: Cells in the log phase of growth were plated in 96-well culture plates in 0.1 ml of complete medium and allowed to adhere overnight at 37 ° C. Compounds diluted in culture medium were added to each well in a volume of 0.1 ml to obtain a final volume of 0.2 ml / well. After the cells were treated with compounds for 96 hours, 0.1 ml of medium was removed and 0.01 ml of MTT reagent was added. Then the tablets were returned to the incubator for 4 hours. Then detergent (0.1 ml) was added and the plates were incubated at 37 ° C. overnight in the dark to dissolve the purple formazin cells and crystals. The optical density was measured at 570 nm. IC Values_fifty for selected compounds are presented in table A.

Table a
IC ₅₀ values (nM) of selected compounds depending on MCF-7, N87, and PC-3 cell lines Compound DNA Class Binding Agent Mcf-7 N87 PC-3 A DB1 0,085 0.156 0.212 B DB1 0,025 0.144 0.145 C DB1 0,037 0.173 0,120 D DB1 0.010 0,087 0.168 E DB1 0,050 0.185 0.176 F DB2 0,093 0.427 0.341 G DB2 0,069 0.556 0.581 H DB6 0,037 0.162 0.166 I DB6 0,050 0.359 0.292

References

Claims (7)

1. The compound of formula (I):

or its pharmaceutically acceptable salt, where
DB is a DNA binding group and is a

,
R ¹ represents halogen;
R ² , R ^{2 ′} , R ³ , R ^{3 ′} , R ⁴ , R ^{4 ′} , R ¹² and R ¹⁹ are H,
X ² represents C (R ¹⁴ ) (R ^{14 ′} ) and where R ^{14 ′} and R ⁷ ′ are absent, which gives a double bond between atoms bearing R ^{7 ′} and R ^{14 ′} ;
R ⁵ , R ⁶ and R ^{7 are} independently selected from H and R ^e , where
R ^{e is} selected from C _1-3 alkyl;
R ^{5 ′} + R ^{6 ′ are} absent, which gives a double bond between atoms bearing R ^{5 ′} and R ^{6 ′} ;
X ¹ represents O;
X ^{3 is} selected from N and NR ¹⁵ ;
X ⁴ represents CR ¹⁶ ;
X ⁵ represents O;
X ^{6 is} selected from CR ¹¹ , CR ¹¹ (R ^{11 ′} ) and N;
X ^{7 is} selected from CR ⁸ , CR ⁸ (R ^{8 ′} ), NR ⁸ and N;
X ^{8 is} selected from CR ⁹ , CR ⁹ (R ^{9 ′} ), NR ⁹ and N;
X ^{9 is} selected from CR ¹⁰ , CR ¹⁰ (R ^{10 ′} ) and N;
X ¹¹ represents C;
X ^{12 is} selected from C and N;
X ³⁴ is C;

implies that said bond may be an optionally delocalized, double bond;
R ⁸ represents H and N (R ^h ) C (O) R ⁱ ;
R ^{8 ′} , R ⁹ , R ^{9 ′} , R ¹⁰ , R ^{10 ′} , R ¹¹ , R ^{11 ′} , R ¹⁵ , R ^{16 ′} represent H,
R ^h represents H;
R ^{i is} selected from C ₆ -C ₉ aryl and indole substituted with one or more substituents selected from OH, NH ₂ , O (CH ₂ CH ₂ O) _2-4 N and O (CH ₂ CH ₂ O) _2-4 CH ₃ ;
a and b are independently selected from 0 and 1;
provided that ring B in DB1 is a heterocycle. 2. The compound according to claim 1, where DB is

3. The compound according to any one of claims 1 or 2, which is a

or a pharmaceutically acceptable salt. 4. The compound according to claims 1 or 2, in which R ⁵ represents methyl, ethyl, propyl, isopropyl. 5. The compound according to any one of claims 1 or 2

. 6. A pharmaceutical composition for treating or preventing a tumor in a mammal, comprising a therapeutically effective amount of a compound according to any one of claims 1 to 5 and a pharmaceutically acceptable carrier. 7. A conjugate for treating or preventing a tumor in a mammal, comprising a compound according to any one of claims 1-5, conjugated to an antibody.

Images